1,3-dioxan-5-ylalkenoic acids

ABSTRACT

The invention concerns novel 4-phenyl-1,3-dioxan-5-ylalkenoic acid derivatives of the formula I having cis relative stereochemistry at positions 4 and 5 of the dioxane ring and wherein Ra and Rb are variously hydrogen, alkyl, halogenoalkyl, alkenyl, and optionally substituted aryl or arylalkyl, Rc is hydroxy, alkoxy or alkanesulphonamido, n is 1 or 2, A is ethylene or vinylene, Y is (2-5C)polymethylene optionally substituted by alkyl, and benzene ring B is optionally substituted phenyl, or, when Rc is hydroxy, a salt thereof. The acid derivatives antagonize one or more of the actions of thromboxane A 2  (TXA 2 ) and are expected to be of value in those disease conditions in which TXA 2  is involved. The invention also provides pharmaceutical compositions containing an acid derivative of formula I, and processes for their chemical production.

This is a division of application Ser. No. 492,247, filed May 6, 1983,now U.S. Pat. No. 4,567,197.

This invention relates to novel 1,3-dioxan-5-ylalkenoic acids and theirderivatives, which antagonise one or more of the actions of thromboxaneA₂ (hereafter referred to as "TXA₂ "), and are valuable therapeuticagents.

It is known that TXA₂ is a potent aggregator of blood platelets and apowerful vasoconstrictor. TXA₂ is also a potent constrictor of bronchialand tracheal smooth muscle. TXA₂ may therefore be involved in a widevariety of disease conditions, for example ischaemic heart disease suchas myocardial infarction and angina, cerebrovascular disease such astransient cerebral ischaemia, migraine and stroke, peripheral vasculardisease such as atherosclerosis, microangiopathy, hypertension and bloodclotting defects due to lipid imbalance, and pulmonary disease such aspulmonary embolism, bronchial asthma, bronchitis, pneumonia, dyspnoeaand emphysema. Accordingly, compounds which antagonise the actions ofTXA₂ may be expected to have therapeutic value in the prevention ortreatment of any one or more of the above mentioned diseases or anyother disease conditions in which it is desirable to antagonise theactions of TXA₂.

Certain 4-substituted-1,3-dioxan-trans-5-ylalkenoic acids typified bythe compound of the formula A [set out, together with the otherstructural formulae referred to herein, on the accompanying formulaesheets] are known (UK Patent application No. 8004647, published as Ser.No. 2046733A) as inhibitors of the enzyme responsible for the synthesisof TXA₂. Similarly, certain 6-alkynyl-b 1,3-dioxan-cis-4-ylalkenoicacids typified by the compound of the formula B are known (Fried etalia, Adv.Prostaglandin and Thromboxane Research, 1980, 6, 427-436) toinhibit various enzymes in the arachidonic acid cascade. However,neither of these groups of 1,3-dioxanylalkenoic acids has been describedas having any antagonist action against the effects of TXA₂.

We have now discovered that the novel, chemically distinct4-substituted-1,3-dioxan-5-ylalkenoic acids and their derivatives, offormula I below, unexpectedly possess the property of antagonising oneor more of the actions of TXA₂ and this is the basis for our invention.

According to the invention there is provided a4-phenyl-1,3-dioxan-cis-5-ylalkenoic acid derivative of the formula Iwherein Ra and Rb are independently hydrogen, (2-6C)alkenyl, (1-8C)alkyloptionally bearing up to three halogeno substituents, pentafluorophenyl,aryl or aryl-(1-4C)alkyl, the latter two of which may optionally bear upto three substituents selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy,(1-4C)alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxy,(2-6C)alkanoyloxy, (1 -6C)alkylthio, (1-6C)alkanesulphonyl,(1-6C)alkanoylamino, and oxapolymethylene of 2 to 4 carbon atoms,provided that when both Ra and Rb are alkyl or alkenyl, the total numberof carbon atoms in Ra and Rb taken together is 8 or less; or Ra and Rbtogether form polymethylene of 2 to 7 carbon atoms, optionally bearingone or two (1-4C)alkyl substituents; Rc is hydroxy, (1-6C)alkoxy or(1-6C)alkanesulphonamido; n is the integer 1 or 2; A is ethylene orvinylene; Y is polymethylene of 2 to 5 carbon atoms optionally bearing(1-4C)alkyl as a substituent; benzene ring B optionally bears one or twosubstituents selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy,hydroxy,(2-6C)alkanoyloxy, (1-6C)alkanoylamino, trifluoromethyl andnitro; and the substituents at positions 4 and 5 of the dioxane ringhave cis-relative stereochemistry; or for those compounds wherein Rc ishydroxy, a salt thereof with a base affording a physiologicallyacceptable cation.

It will be appreciated that the compounds of formula I contain at leasttwo asymmetric carbon atoms (i.e. at C₄ and C₅ of the dioxane ring) andmay exist and be isolated in racemic and optically active forms. Inaddition those compounds of formula I wherein A is vinylene exist, andmay be isolated, in separate stereoisomeric forms (`E` and `Z`) aboutthat group. It is to be understood that the present inventionencompasses any racemic, optically active or stereoisomeric form (ormixtures thereof) which is capable of antagonising one or more of theactions of TXA₂, it being well known in the art how to prepareindividual optical isomers (for example by synthesis from opticallyactive starting materials or resolution of a racemic form) andindividual `E` and `Z` stereoisomers (for example by chromatographicseparation of a mixture thereof), and how to determine the TXA₂antagonist properties using the standard test described hereafter.

In this specification, the terms Ra, Rb and Rc etc, are used to depictgeneric radicals and have no other significance.

A particular value for Ra or Rb when it is (1-8C)alkyl is, for example,methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl or octyl,and when it is (1-8C)alkyl bearing up to three halogeno atoms is, forexample chloromethyl, 2-chloroethyl, trifluoromethyl or2,2,2-trifluoroethyl.

A particular value for Ra or Rb when it is aryl is, for example, phenyl,1-naphthyl or 2-naphthyl; when it is aryl-(1-4C)alkyl is, for example,benzyl, 1-phenylethyl or 2-phenylethyl; and when it is (2-6C)alkenyl is,for example, vinyl, allyl or 2-methylallyl.

Particular values for optional substituents, which may be present onbenzene ring B or on an aromatic moiety which constitutes or is part ofRa or Rb as defined above, are, for example:

for halogeno: fluoro, chloro, bromo or iodo;

for (1-6C)alkyl: methyl, ethyl, propyl or isopropyl;

for (1-6C)alkoxy: methoxy, ethoxy or propoxy;

for (1-4C)alkylenedioxy: methylenedioxy, ethylenedioxy orisopropylidenedioxy;

for (1-6C)alkylthio: methylthio or ethylthio;

for (1-6C)alkanesulphonyl: methanesulphonyl or ethanesulphonyl;

for (1-6C)alkanoylamino: formamido, acetamido or propionamido;

for (2-6C)alkanoyloxy: acetoxy or propionyloxy; and

for oxapolymethylene of 2 to 4 carbon atoms, a group of the formula--CH₂ OCH₂ -- or --CH₂ CH₂ OCH₂ --.

In general when one of Ra and Rb is hydrogen it is preferred that theother of Ra and Rb is arranged so as to have cis-relativestereochemistry with reference to the substituents at positions 4 and 5of the dioxane ring.

A particular value for Ra and Rb when together they form polymethyleneof 2 to 7 carbon atoms is, for example, ethylene, trimethylene,tetramethylene, pentamethylene or hexamethylene; and a particular valuefor an optional (1-4C)alkyl substituent thereon is, for example, methyl.

A particular value for Rc when it is (1-6C)alkanesulphonamido is, forexample, methanesulphonamido, ethanesulphonamido, propanesulphonamido or1-methylethanesulphonamido.

A particular value for Rc when it is (1-6C)alkoxy is, for example,methoxy or ethoxy.

A particular value for Y is, for example, ethylene, trimethylene ortetramethylene; and a particular value for an optional substiuentthereon is, for example, methyl.

Specific examples of Ra and Rb are, for example, hydrogen, methyl,ethyl, propyl, isopropyl, butyl, pentyl, hexyl, octyl, vinyl, allyl,2-methylallyl, trifluoromethyl, chloromethyl, 2-chloroethyl, phenyloptionally bearing a fluoro, chloro, bromo, methyl, methoxy,trifluoromethyl, methylthio, methanesulphonyl, nitro, hydroxy, cyano,acetamido, methylenedioxy or a methyleneoxymethylene (--CH₂ OCH₂ --)substituent, dichlorophenyl, dimethylphenyl, pentafluorophenyl,1-naphthyl, 2-naphthyl or benzyl; or are, for example, when theytogether form trimethylene, pentamethylene or hexamethylene, optionallybearing a methyl substituent.

Specific values for benzene ring B are, for example, when it is phenyl,2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-methoxyphenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-hydroxyphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-fluorophenyl,3-chlorophenyl, 4-fluorophenyl, 4-methylphenyl or 2,6-difluorophenyl.

A preferred value for Rc is, for example, hydroxy, methoxy, ethoxy,methanesulphonamido or ethanesulphonamido, of which hydroxy isespecially preferred.

A preferred value for A is vinylene, and for Y is, for example,trimethylene. A preferred value for n is the integer 1.

In general when A is vinylene it is preferred that the adjacent carbonatoms have cis-relative stereochemistry i.e. the `Z` configuration.

A preferred value for benzene ring B is, for example, when it isunsubstituted; ortho-substituted by fluoro, chloro, methyl, hydroxy,methoxy, ethyl or isopropyl; or meta-substituted by fluoro or chloro.

A preferred group of acid derivatives of the invention comprises thosecompounds of formula Ia wherein Ra and Rb are:

(i) independently hydrogen or (1-4C)alkyl, optionally bearing 1 to 3halogeno substituents;

(ii) one of the two is hydrogen or (1-4C)alkyl, and the other is phenyl,naphthyl or phenyl-(1-4C)alkyl, optionally bearing 1 or 2 substituentsselected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylenedioxy,trifluoromethyl, cyano, nitro, hydroxy, (2-4C)alkanoyloxy,(1-4C)alkylthio, (1-4C)alkanesulphonyl, (1-4C)alkanoylamino andoxapolymethylene of 2 to 4 carbon atoms, or pentafluorophenyl;

(iii) one of the two is hydrogen and the other is (5-8C)alkyl or(2-6C)alkenyl; or

(iv) both together form polymethylene of 2 to 7 carbon atoms optionallybearing a (1-4C)alkyl substituent;

Rc is hydroxy, (1-4C)alkoxy or (1-4C)alkanesulphonamido; and benzenering B optionally bears a single substituent located at the 2-positionselected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy,(2-4C)alkanoyloxy, (1-4C)alkanoylamino and trifluoromethyl, or bears a3-halogeno substituent; and the substituents at positions 4 and 5 of thedioxane ring have cis-relative stereochemistry; or for those compoundswherein Rc is hydroxy, a salt thereof with a base affording aphysiologically acceptable cation.

Particular values for the various substituents in the above preferredgroup are, for example:

for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl or butyl;

for (5-C)alkyl: pentyl, hexyl, heptyl or octyl;

for (1-84C)alkoxy: methoxy or ethoxy;

for (1-4C)alkyl bearing 1 to 3 halogeno substituents: chloromethyl,2-chloroethyl, 2,2,2-trifluoroethyl or trifluoromethyl;

for phenyl-(1-4C)alkyl: benzyl, 2-phenylethyl or 1-phenylethyl;

for halogeno: fluoro, chloro or bromo:

for (1-4C)alkylenedioxy: methylenedioxy, ethylenedioxy orisopropylidenedioxy;

for (2-4C)alkanoyloxy: acetoxy or propionyloxy;

for (1-4C)alkylthio: methylthio or ethylthio;

for (1-4C)alkanesulphonyl: methanesulphonyl or ethanesulphonyl;

for (1-4C)alkanoylamino: acetamido or propionamido; and

for oxapolymethylene of 2 to 4 carbon atoms: methyleneoxymethylene(--CH₂ OCH₂) or ethyleneoxy (--CH₂ CH₂ O--).

Specific combinations of Ra and Rb which are preferred are, by way ofexample:

(i) Ra and Rb are both hydrogen, methyl, ethyl, propyl, butyl ortrifluoromethyl;

(ii) one of Ra is hydrogen and the other is trifluoromethyl,chloromethyl, benzyl, isopropyl, hexyl, octyl, phenyl (optionallybearing 1 or 2 fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl,hydroxy, cyano, methylthio or acetamido), phenyl bearing methylenedioxyor methyleneoxymethylene (--CH₂ OCH₂ --), pentafluorophenyl, 1-naphthylor 2-naphthyl; and

(iii) Ra and Rb together form trimethylene, tetramethylene,pentamethylene, hexamethylene or a group of the formula: --CH₂ CH₂.CHCH₃. CH₂ CH₂ --.

Specific preferred values for Ra or Rb when it is a mono ordisubstituted phenyl are, for example, 2-fluoro-, 3-fluoro-, 4-fluoro-,2-chloro-, 3-chloro-, 4-chloro-, 2-bromo-, 3-bromo-, 4-bromo-,2-methyl-, 3-methyl-, 4-methyl-, 2-methoxy-, 3-methoxy-, 4-methoxy-,2-trifluoromethyl-, 3-trifluoromethyl-, 4-trifluoromethyl-, 3-hydroxy-,4-cyano-, 4-methylthio-, 4-acetamido-, 3,4-dichloro-, 2,4-dimethyl-,3,4-methylenedioxy- and 3,4-(methyleneoxymethylene)-phenyl.

Specific preferred values for benzene ring B are, for example, when itis phenyl, or 2-fluoro-, 2-chloro-, 2-bromo-, 2-methyl-, 2-ethyl-,2-isopropyl-, 2-methoxy-, 2-hydroxy-, 3-fluoro- or 3-chloro-phenyl.

A further preferred group of acids of the invention comprises compoundsof the formula Ib wherein:

(i) Ra and Rb are both hydrogen, methyl, ethyl, propyl, butyl, ortrifluoromethyl;

(ii) or together form trimethylene, tetramethylene, pentamethylene,hexamethylene or a group of the formula: --CH₂ CH₂. CHCH₃. CH₂ CH₂ --;or

(iii) Ra is (3-8C)alkyl, trifluoromethyl, chloromethyl, 1-chloroethyl,pentafluorophenyl, or phenyl, benzyl or naphthyl, the last three ofwhich may optionally bear 1 or 2 halogeno, (1-4C)alkyl, (1-4C)alkoxy,trifluoromethyl, hydroxy, cyano, (1-4C)alkylthio or (1-4C)alkanoylaminosubstituents, or a methylenedioxy or methyleneoxymethylene substituent,and Rb is hydrogen;

benzene ring B is unsubstituted or is 2-halogeno-, 2-(1-4C)alkyl-,2-(1-4C)alkoxy-, 2-hydroxy-or 3-halogeno-phenyl;

Ra and the substituents at the 4 and 5-positions of the dioxane ringhave cis-relative stereochemistry; and the carbon atoms adjacent to thevinylene group have the indicated cis-relative stereochemistry; or asalt thereof with a base affording a physiologically acceptable cation;or a methyl or ethyl ester thereof; or a methanesulphonamido,ethanesulphonamido or 1-methylethanesulphonamido derivative thereof.

A preferred value for Ra when it is (3-8C)alkyl is, for example,isopropyl, butyl, hexyl or octyl.

Preferred values for substituents on Ra when it is phenyl, benzyl ornaphthyl are, for example:

for halogeno: fluoro, chloro or bromo;

for (1-4C)alkyl: methyl;

for (1-4C)alkoxy: methoxy;

for (1-4C)alkylthio: methylthio; and

for (1-4C)alkanoylamino: acetamido.

Preferred values for substituents on benzene ring B are, for example:

for 2-halogeno: 2-fluoro, 2-chloro or 2-bromo;

for 3-halogeno: 3-fluoro or 3-chloro;

for 2-(1-4C)alkyl: 2-methyl, 2-ethyl or 2-isopropyl; and

for 2-(1-4C)alkoxy: 2-methoxy.

Particular salts of compounds of formula I wherein Rc is hydroxy are,for example, alkali metal and alkaline earth metal salts such aslithium, sodium, potassium, magnesium and calcium salts, aluminium andammonium salts, and salts with organic amines or quaternary basesforming physiologically acceptable cations, such as salts withmethylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine,morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine,N-methylglucamine, tetramethylammonium hydroxide andbenzyltrimethylammonium hydroxide.

Specific compounds of the invention are described in the accompanyingExamples and of these a compound of particular interest is5(Z)-7-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid or apharmaceutically acceptable salt thereof.

The compounds of formula I may be manufactured by conventionalprocedures of organic chemistry well known in the art for the productionof analogous compounds. Such processes are provided as a further featureof the invention and are illustrated by the following preferredprocedures in which Ra, Rb, Rc, benzene ring B, n, A and Y have any ofthe meanings defined hereinbefore:

(a) For a compound wherein Rc is hydroxy and A is vinylene, reacting analdehyde of the formula II with a Wittig reagent of the formula:

    (Rd).sub.3 P═CH.Y.CO.sub.2.sup.- M.sup.+               III

wherein Rd is (1-6C)alkyl (especially methyl or ethyl) or aryl(especially phenyl), and M⁺ is, for example, an alkali metal cation suchas the lithium, sodium or potassium cation.

The process in general produces compounds of formula I in which thecarbon atoms adjacent to the vinylene have predominantly cis-relativestereochemistry i.e. the "Z" isomer. However the compounds of formula Ihaving trans-relative stereochemistry (i.e. the "E" isomer) are alsoformed in the process and may be obtained by conventional separation ofthe mixture of "Z"- and "E"- isomers first obtained.

The process is conveniently performed in a suitable solvent or diluent,for example an aromatic solvent such as benzene, toluene orchlorobenzene, an ether such as 1,2-dimethoxyethane, dibutyl ether,tetrahydrofuran, dimethyl sulphoxide or tetramethylene sulphone, or in amixture of one or more such solvents or diluents. The process isgenerally performed at a temperature in the range, for example, -80° C.to 40° C. but is conveniently performed at or near room temperature,that is in the range 15° to 35° C.

If desired the proportion of the product of the process with trans-relative stereochemistry about the double bond may frequently beincreased by choice of a suitable solvent, for example tetramethylenesulphone, and/or addition of an alkali halide, for example lithiumbromide, to the reaction mixture.

The starting Wittig reagents of formula III are in general well known inthe art or may be obtained by analogous procedures. They are generallyformed by treatment of the corresponding phosphonium halides with astrong base such as sodium hydride, lithium diisopropylamide, potassiumt-butoxide or butyl lithium in a suitable solvent such as that used forthe process itself, and are generally formed in situ immediately priorto carrying out process (a).

The starting materials of formula II may be obtained by the sequencesshown in Schemes 1 or 2, (attached hereafter, many of which areillustrated in the accompanying Examples). ##STR1##

These sequences involve selective conversions of functional groups whichare well known in the synthesis of structurally analogous compounds,such as the prostaglandins and their analogues and, in general, similarreaction conditions to those well known in the art are used. Forexample, when alkylthio substituents are to be present then anappropriate sequence is used which avoids a non-specific oxidation step(e.g. step (v) of Scheme I and step (vi) of Scheme 2. Similarly, when ahydroxy substituent is to be present on benzene ring B then a startingmaterial of formula IV may be used in which the hydroxy substituent hasbeen protected for example as its trimethylsilyl ether. The protectinggroup is then removed, for example by reaction with tetrabutylammoniumfluoride, in a conventional manner as a final step prior to carrying outprocess (a). Similarly, when an acyloxy substituent is to be present onbenzene ring B, this may be produced by acylation of the correspondinghydroxy derivative of formula II using a conventional procedure as afinal step.

It will be seen that a mixture of stereoisomers at positions 4,5 of thedioxane rings is generally obtained from Scheme 1 and that it isnecessary to separate out the required cis-stereoisomer, convenientlyafter cyclisation of the 5-allyl-1,3-dioxanes VII, using a conventionalprocedure such as chromatography.

The 5-allyl-1,3-dioxanes VII may also be obtained by an acetal exchangereaction analogous to that described in process (b), for example byreacting [4,5-cis]-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane with anexcess of the appropriate ketone or aldehyde of the formula RaRb.CO (orits dimethyl acetal or ketal) in the presence of p-toluenesulphonicacid. This procedure and related alternatives are described in theaccompanying Examples.

The keto esters IV may be obtained by conventional organic syntheses asillustrated in the accompanying Examples.

(b) Reacting an erythro-diol derivative of the formula XIII wherein oneof Qa and Qb is hydrogen and the other is hydrogen, alkanesulphonyl,arenesulphonyl or a group of the formula --CRR¹.OH wherein R and R¹ arethe same or different alkyl, with a carbonyl compound of the formulaRaRb.CO, or an acetal, hemiacetal or hydrate thereof.

A suitable value for Qa or Qb when it is alkanesulphonyl is, forexample, methanesulphonyl or ethanesulphonyl and when it isarenesulphonyl is, for example, benzenesulphonyl or p-toluenesulphonyl.A suitable value for R or R¹ is, for example, methyl or ethyl.

The carbonyl compound of the formula RaRb.CO (or its hydrate, or itsacetal or hemiacetal with a (1-4C)alkanol) is preferably used in excess.

Depending on the nature of Qa and Qb different reaction conditions arenecessary. Thus, when Qa and Qb are both hydrogen or when one is a groupof the formula --CRR¹.OH and the other is hydrogen, the reaction iscarried out in the presence of an acid catalyst, for example, hydrogenchloride, hydrogen bromide, sulphuric acid, phosphoric acid,p-toluenesulphonic acid or the anionic form of a sulphonated polystyrenecatalyst, conveniently in a suitable solvent or diluent, for example anether such as diethyl ether, dibutyl ether, 1,2-dimethoxyethane ortetrahydrofuran, and at a temperature in the range, for example, 10° to12° C. The acid catalyst may also be provided by the inherent acidity ofthe starting material of formula XIII wherein Rc is hydroxy, asillustrated in Example 8 hereafter.

Similarly, when one of Qa and Qb is alkanesulphonyl or arenesulphonyland the other is hydrogen, the reaction is carried out first in thepresence of an acid catalyst, for example under the conditions describedabove to produce an intermediate of the formula XIII, wherein one of Qaand Qb is alkanesulphonyl or arenesulphonyl, and the other is a group ofthe formula --CRaRb.OH. The latter intermediate may then be cyclised insitu to the required compound of formula I by addition of a strong base,for example, sodium hydride or butyl lithium, in a suitable solvent ordiluent, for example in the ether solvent used for the acid catalysedstep above, and at a temperature in the range, for example, 30°-100° C.

It will be appreciated that the above mentioned intermediate may also beisolated, characterised and separately cyclised under the influence ofstrong base to give a compound of formula I. Such a procedure isencompassed by the invention.

Those starting materials of formula XIII wherein Qa and Qb are bothhydrogen (that is an erythrodiol of formula XIII) may be obtained bymild hydrolysis or alcoholysis of the dioxane ring of a compound offormula I, for example, in which Ra and Rb are both methyl or ethylradicals, obtained by another process described herein. This reactionwill normally be carried out at a temperature in the range, for example,25°-100° C. and preferably in the range 30°-60° C., using an aqueousmineral acid such as hydrochloric acid in an alcoholic solvent such asethanol or 2-propanol. Those starting materials of formula XIII whereinone of Qa and Qb is a group of the formula --CRR¹.OH and the other ishydrogen, are generally obtained as intermediates in the above mentionedformation of the erythro-diol of formula XIII (Qa═Qb═H) and are notnormally isolated or characterised. Accordingly, the invention alsoprovides a process which comprises reacting a compound of formula I forexample wherein Ra and Rb are methyl or ethyl, with an excess of acompound of the formula RaRb.CO in the presence of an acid-catalyst(such as those mentioned above), conveniently in a suitable solvent ordiluent (such as an ether mentioned above) and at a temperature in therange for example 10° to 120° C.

Those starting materials of formula XIII wherein one Qa and Qb isalkanesulphonyl or arenesulphonyl and the other is hydrogen, may beobtained from the corresponding erythro- diol of formula XIII (Qa═Qb═H)by reaction with one molecular equivalent of the appropriatealkanesulphonyl or arenesulphonyl halide, for example methanesulphonylchloride or p-toluenesulphonyl chloride, in a suitable solvent ordiluent (such as an ether or dichloromethane) and in the presence of abase such as pyridine or trriethylamine.

The erythro-diols of formula XIII (Qa═Qb═H A═vinylene, Rc═OH) mayalternatively be obtained by carrying out the Wittig reaction in process(a) hereinbefore using a trimethylsilylated aldehyde of the formula XIV(itself prepared, for example, by replacing step (iii) in Scheme 1 by aconventional silylation procedure) and then removing the trimethylsilylprotecting groups in a conventional manner, for example withtetrabutylammonium fluoride, from the Wittig reaction product of theformula XV. When a starting material of formula XIII wherein Rc is otherthan hydroxy is required, the carboxylic acid group of the Wittigreaction product XV may be derivatised by the procedures describedhereinafter, prior to the removal of the trimethylsilyl protectinggroups.

The starting materials of formula XIII wherein A is ethylene may beobtained by conventional hydrogenation of the corresponding compoundswherein A is vinylene.

Process (b) is not normally suitable for the production of compounds offormula I wherein both Ra and Rb are trifluoromethyl.

Under some circumstances when Rc is hydroxy in the starting materials offormula XIII, some degree of concomitant esterification may occur duringprocess (b) (see Example 83 hereafter), such that hydrolysis [accordingto process (d) hereafter] of the reaction product may be necessary inorder to obtain the required compound of formula I wherein Rc ishydroxy.

The necessary starting ketones of formula RaRb.CO and their derivativesare generally already known or may readily be obtained by standardtechniques of organic chemistry.

(c) For a compound of formula I wherein Rc is hydroxy, oxidising analcohol of the formula XVI.

A range of oxidising agents is suitable for use in this process, forexample, chromium trioxide in aqueous sulphuric acid and acetone;platinum and oxygen in aqueous acetone or tetrahydrofuran; or alkalinepersulphate in the presence of ruthenium trichloride. A suitable solventor diluent which is compatible with the oxidising agent may convenientlybe employed.

The process may be carried out at a temperature in the range, forexample 10° to 50° C., but is preferably performed at or near roomtemperature in order to minimise the risk of oxidation of othersensitive substituents in the molecule. Equally, where such substituentsare present, the process may be conveniently performed in two stepsusing two oxidising agents, that is by intermediate formation of thecorresponding aldehyde of the formula XVII using an oxidising agent suchas pyridinium chlorochromate (preferably in a solvent such asdichloromethane), or the Pfitzner-Moffatt reagent(dicyclohexylcarbodiimide and dimethyl sulphoxide in the presence of anacid catalyst for example pyridine trifluoroacetate), in both cases ator near room temperature. The aldehyde of formula XVII may then beseparately oxidised to the required carboxylic acid of formula I (Rc═OH)by reaction with a mild oxidising agent such as silver oxide in thepresence of an alkali metal hydride such as sodium hydroxide,conveniently in a solvent or diluent, for example a (1-4C)alkanol suchas ethanol, and at or near room temperature. This latter process is alsoprovided as a feature of the invention.

The starting materials of formula XVI wherein A is a vinylene radicalmay be obtained by analogy with process (a) but using a Wittig reagentof the formula:

    (Rd).sub.3 P═CH.Y.CH.sub.2.O.Si(CH.sub.3).sub.3

(wherein Rd has the meaning defined previously) and an aldehyde offormula II and then removing the trimethylsilyl protecting group in aconventional manner from the product to give the required alcohol offormula XVI. Similarly those starting materials of formula XVI wherein Ais ethylene may be obtained by conventional hydrogenation of thecorresponding compounds of formula XVI wherein A is vinylene.

(d) For a compound of formula I wherein Rc is hydroxy, hydrolysing acompound of the formula XVIII wherein W is alkoxycarbonyl,phenoxycarbonyl, benzyloxycarbonyl, cyano or carbamoyl.

A particular value for W when it is alkoxycarbonyl is methoxycarbonyl orethoxycarbonyl.

The hydrolysis is conveniently carried out under the influence of base,for example an alkali metal hydroxide (such as sodium or potassiumhydroxide) in a suitable aqueous solvent, for example a (1-4C)alkanol(such as methanol or ethanol) or a glycol (such as ethylene glycol) at atemperature in the range, for example, 15° to 15° C. In general, higherreaction temperatures are required when W is cyano or carbamoyl, forexample in the range 80°-150° C.

The starting materials of formula XVIII wherein W is cyano may beobtained by reaction of an alcohol of the formula XIX withmethanesulphonyl chloride in a suitable solvent such as dichloromethanein the presence of a base such as triethylamine to give the mesylate ofthe formula XX, which is then reacted with potassium cyanide in dimethylsulphoxide at 50°-100° C. The starting alcohols of formula XIX maythemselves be obtained by analogy with those of formula XVI in process(c) hereinbefore by using a Wittig reagent of the formula:

    (Rd).sub.3 P═CH.Y.O.Si(CH.sub.3).sub.3

wherein Rd has the meaning defined previously. When A is ethylene thealcohol of formula XIX may be hydrogenated prior to reaction withmethanesulphonyl chloride.

The necessary starting materials of formula XVIII may be obtained byanalogy with other processes described herein.

(e) For a compound of formula I wherein Ra, Rb or benzene ring B bears ahydroxy substituent, deprotecting a corresponding derivative of saidcompound wherein the hydroxy substituent is protected by atrimethylsilyl, (1-6C)alkyl (such as methyl or ethyl) or acyl (such asacetoxy or benzoyloxy) protecting group.

The deprotection conditions required necessarily depend on theprotecting groups concerned. Thus, for example, when it is methyl orethyl (i.e. the starting material is the corresponding methoxy or ethoxycompound of formula I) the deprotection may be carried out, for example,by heating with sodium thioethoxide in a suitable solvent (such asN,N-dimethylformamide) at an elevated temperature, for example 90°-160°C. Similarly, when the protecting group is acyloxy, it may be removed,for example by hydrolysis in the presence of a base (such as sodium orpotassium hydroxide) in a suitable aqueous solvent [such as a(1-4C)alkanol or a glycol] at a temperature in the range, for example,10°-60° C. Similarly in the case of a trimethylsilyl protecting group,it may be removed for example, by reaction with aqueoustetrabutylammonium fluoride or sodium fluoride in conventional manner.

The necessary protected derivatives of the formula I compounds may bemade by analogy with the other processes described herein.

(f) For a compound of formula I wherein Ra and Rb are both hydrogen,reacting an erythro-diol of the formula XIII wherein Qa and Qb are bothhydrogen, with methylene bromide in the presence of base.

A particularly suitable base is for example, sodium or potassiumhydroxide, or sodium hydride.

The process is preferably carried out in a suitable solvent or diluent,for example dimethyl sulphoxide, and at a temperature in the range, forexample, 10° to 40° C., conveniently at or near room temperature.

When a compound of formula I wherein Rc is (1-6C)alkoxy is required, thecorresponding acid of formula I wherein Rc is hydroxy, or a reactivederivative thereof, is esterified using a conventional procedure.

Thus, for example, an acid of formula I wherein Rc is hydroxy, or areactive derivative thereof, may be esterified by reaction with theappropriate (1-6C)alkanol.

It will be appreciated that when a free acid of formula I is used in theprocess, water is produced during the reaction. Consequently, in suchcases it is particularly convenient to perform the process in thepresence of a suitable dehydrating agent, for exampledicyclohexylcarbodiimide, in the presence of a suitable solvent ordiluent for example tetrahydrofuran, acetone, methylene chloride or1,2-dimethoxyethane, at a temperature in the range, for example, 10° to50° C., but preferably at or near room temperature.

A suitable reactive derivative of an acid of formula I is, for example,an acid chloride, bromide, anhydride, mixed anhydride with formic acid,or an azide, which may be produced from the free acid in conventionalmanner. When such a derivative is used in the process, no additionaldehydrating agent is necessary, and the (1-6C)alkanol is convenientlyused in large excess, optionally diluted with a suitable diluent orsolvent such as an ether, for example tetrahydrofuran or1,2-dimethoxyethane.

In general, when a reactive derivative of an acid of formula I is usedno external heating of the reaction is necessary.

When a compound of formula I wherein Rc is (1-6C)alkanesulphonamido isrequired, the corresponding acid of formula I wherein Rc is hydroxy, ora reactive derivative thereof, is reacted with the appropriate(1-6C)alkanesulphonamide.

Thus, for example a free acid of formula I wherein Rc is hydroxy may bereacted with a suitable dehydrating agent, for exampledicyclohexylcarbodiimide, optionally together with an organic base, forexample 4-dimethylaminopyridine, in the presence of a suitable solventor diluent, for example methylene chloride at a temperature in therange, 10° to 50° C., but preferably at or near room temperature.Alternatively, a reactive derivative of an acid of formula I, wherein Rcis hydroxy, for example an acid halide (such as the acid chloride) maybe reacted with an alkali metal salt (such as the sodium salt) of theappropriate (1-6C)alkanesulphonamide, conveniently at or near roomtemperature and in a suitable solvent or diluent, for example an ether,N,N-dimethylformamide or methylene chloride.

When a compound of formula I wherein A is ethylene is required, thecorresponding compound of formula I wherein A is vinylene ishydrogenated, in the presence of a catalyst.

The hydrogenation may be carried out in a suitable solvent or diluent,for example a (1-4C)alkanol (such as ethanol or 2-propanol), optionallyin the presence of water, and at a temperature in the range, forexample, 15° to 35° C., using hydrogen at a pressure of, for example, 1to 2 atmospheres.

A suitable catalyst is, for example, a noble metal catalyst such aspalladium metal conveniently on an inert support such as carbon, bariumsulphate or barium carbonate.

When a salt of a compound of formula I wherein Rc is hydroxy isrequired, it is obtained by reaction with the appropriate base affordinga physiologically acceptable cation, or by any other conventionalprocedure.

Further, when an optically active form of a compound of formula I isrequired, one of the aforesaid processes is carried out using anoptically active starting material. Alternatively, when Rc is hydroxy, aracemic form of the said compound may be reacted with an opticallyactive form of a suitable organic base, for example ephedrine,N,N,N-trimethyl (1-phenylethyl)ammonium hydroxide or 1-phenylethylamine,followed by conventional separation of the diastereoisomeric mixture ofsalts thus obtained, for example by fractional crystallisation from asuitable solvent, for example a (1-4C)alkanol, whereafter the opticallyactive form of said compound of formula I may be liberated by treatmentwith acid using a conventional procedure for example using an aqueousmineral acid such as dilute hydrochloric acid.

When an optically active form of a compound of formula I wherein Rc isother than hydroxy is required, it may be obtained using theaforementioned esterification or amidification procedures using theappropriate optically active form of said acid.

The intermediates of formula II and VII as defined hereinbefore arenovel and are provided as further separate features of the invention.

As stated earlier, the compounds of formula I are antagonists of one ormore of the actions of TXA₂, for example certain of its actions on bloodplatelets, the vasculature and/or the lung. The antagonism may bedemonstrated in one or other of the following tests:

(a) The standard rabbit aortal strip model devised by Piper and Vane(Nature, 1969, 233, 29-35) using as agonist a freshly prepared sample ofTXA₂, generated by addition of arachidonic acid (25 μg.) to citrated,platelet rich rabbit plasma (250 μl.) and allowing the mixture toaggregate fully over 90 seconds before use;

(b) a standard blood platelet aggregation test based on that describedby Born (Nature, 1962, 194, 927-929) and involving measuring theinhibition by a test compound of aggregation of citrated, platelet richhuman plasma induced by a sub-maximal concentration (in the range 25-100μg/ml.) of arachidonic acid; and

(c) a standard bronchoconstriction test involving measuring theinhibition by a test compound of the bronchoconstriction induced in theKonzett-Rossler guinea-pig model (as modified by Collier and James,Brit. J. Pharmacol., 1967, 30, 283-307) by intravenous administration ofthe TXA₂ mimetic agent, U46619 at 1-1.5 μg./kg.

By way of illustration only, the compound of the formula I,5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acidpossessed the following properties in the above tests:

(a) pA₂ 6.28;

(b) IC₅₀ ca 6.7×10⁻⁵ M; and

(c) 90% reduction of bronchoconstriction at 5 mg./kg. i.v. In general,other compounds of formula I show similar or better levels of activityin test (a) [pA₂ 5.0], and in at least one of tests (b) and (c) withoutany signs of overt toxicity at the active dose in test (c).

Similarly, the following representative group of acids of formula Ibshow significant activity in test (a) [pA₂ ≧5.9] and oral activity at 50mg./kg.(or much less) in test (c) without any signs of overt toxicity:

    ______________________________________                                                                       Benzene                                        Compound                                                                              Ra             Rb      Ring B                                         ______________________________________                                        1       Ethyl          Ethyl   Phenyl                                         2       Pentamethylene     Phenyl                                             3       Methyl         Methyl  3-Fluorophenyl                                 4       Methyl         Methyl  3-Chlorophenyl                                 5       Methyl         Methyl  2-Methoxyphenyl                                6       Methyl         Methyl  Phenyl*                                        7       Ethyl          Ethyl   2-Fluorophenyl                                 8       Hexamethylene      Phenyl                                             9       (3-Methyl)pentamethylene                                                                         Phenyl                                             10      Trifluoromethyl                                                                              H       Phenyl                                         11      2-Chlorophenyl H       Phenyl                                         12      3-Chlorophenyl H       Phenyl                                         13      4-Chlorophenyl H       Phenyl                                         14      3-Fluorophenyl H       Phenyl                                         15      4-Fluorophenyl H       Phenyl                                         16      2-Methylphenyl H       Phenyl                                         17      2-Ethylphenyl  H       Phenyl                                         18      4-Methoxyphenyl                                                                              H       Phenyl                                         19      3-Methylthiophenyl                                                                           H       Phenyl                                         20      Isopropyl      H       Phenyl                                         21      3,4-Methylenedioxy-                                                                          H       Phenyl                                                 phenyl                                                                22      3,4-(Methyleneoxy-                                                                           H       Phenyl                                                 methylene)phenyl                                                      23      Methyl         H       Phenyl                                         24      Methyl         Methyl  2-Methylphenyl                                 25      Methyl         Methyl  2-Hydroxyphenyl                                ______________________________________                                         *methanesulphonamido derivative.                                         

The antagonism of the effects of TXA₂ on the vasculature may bedemonstrated in the following manner:

Male rats (Alderley Park strain) are anaesthetised with sodiumpentabarbital and blood pressure is monitored at the carotid artery. TheTXA₂ mimetic agent known as U46619 (e.g. R. L. Jones, et alia, in"Chemistry, Biochemistry and Pharmacological Activity of Prostanoids"eds. S. M. Roberts and F. Scheinmann, at p.211; Pergamon Press, 1979) isadministered intravenously via the jugular vein and an ED₅₀ (dosenecessary to produce 50% of the maximum hypertensive effect) inestablished (n═3). The ED₅₀ for U46619 is approximately 5 μg./kg. A testcompound is then administered either intravenously via the jugular veinor orally via a cannula directly into the stomach and the animalchallenged with an ED₅₀ dose of U46619, five minutes after dosing withtest compound and then successively every ten minutes until thehypertensive effect of U46619 is no longer blocked.

By way of illustration only, in this test the laevorotatory form of5(Z)-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid showedsignificant reduction (>30%) of the hypertensive effects of the TXA₂mimetic U46619 for a period of 120 minutes after oral administration at50 mg./kg. However, in general preferred compounds of formula I showsignificant reduction of the hypertensive effect of U46619, for examplefor at least 60 minutes after intravenous administration at 10 mg./kg.or less, without any signs of overt toxicity at the active dose. Otherillustrative compounds of the invention which may be mentioned asshowing significant reduction of the hypertensive effects of U46619 forat least 60 minutes after oral administration in the above test are, forexample, compounds 1, 2, 3, 5, 11, 13, 20, 21, 23 and 24 in the abovelist.

As stated previously, the compounds of formula I may be used in thetherapy or prevention of diseases or adverse conditions in warm-bloodedanimals in which it is desirable to antagonise one or more of theactions of TXA₂. In general, a compound of formula I will beadministered for this purpose by an oral, rectal, intravenous,subcutaneous, intramuscular or inhalation route, so that a dose in therange, for example 0.5-20 mg./kg. body weight, will be given up to fourtimes per day, varying with the route of administration, the severity ofthe condition and the size and age of the patient under treatment.

The compounds of formula I will generally be used in the form of apharmaceutical composition comprising a compound of formula I or, whereappropriate, a salt thereof as defined hereinbefore, together with apharmaceutically acceptable diluent or carrier. Such compositions areprovided as a further feature of the invention and may be in a varietyof dosage forms. For example, they may be in the form of tablets,capsules, solutions or suspensions for oral administration; in the formof suppositories for rectal administration; in the form of sterilesolutions or suspensions for administration by intravenous orintramuscular injection; in the form of aerosols or nebuliser solutionsor suspensions for administration by inhalation; and in the form ofpowders together with pharmaceutically acceptable inert solid diluentssuch as lactose for administration by insufflation.

The pharmaceutical compositions may be obtained by conventionalprocedures using pharmaceutically acceptable diluents and carriers wellknown in the art. Tablets and capsules for oral administration mayconveniently be formed with an enteric coating, for example comprisingcellulose acetate phthalate, to minimise contact of the activeingredient of formula I with stomach acids.

The pharmaceutical compositions of the invention may also contain one ormore agents known to be of value in diseases or conditions intended tobe treated; for example, a known platelet aggregation inhibitor,hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker ora vasodilator may usefully also be present in a pharmaceuticalcomposition of the invention for use in treating a heart or vasculardisease or condition. Similarly, by way of example, an anti-histamine,steroid (such as beclomethasone dipropionate), sodium cromoglycate,phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefullyalso be present in a pharmaceutical composition of the invention for usein treating a pulmonary disease or condition.

In addition to their use in therapeutic medicine the compounds offormula I are also useful as pharmacological tools in the developmentand standardisation of test systems for the evaluation of the effects ofTXA₂ in laboratory animals such as cats, dogs, rabbits, monkeys, ratsand mice, as part of the search for new therapeutic agents. Thecompounds of formula I may also be used because of their TXA₂ antagonistproperties in helping to maintain the viability of blood and bloodvessels in warm-blooded animals (or parts thereof) under-goingartificial extracorporeal circulation, for example during limb or organtransplants. When used for this purpose a compound of formula I or aphysiologically acceptable salt thereof will generally be administeredso that a steady state concentration in the range, for example, 0.5 to50 mg. per liter is achieved in the blood.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in therange 18°-26° C.;

(iii) column chromatography was performed on Merck Kieselgel 60 (Art,7734) using approximately 50-70 g. of SiO₂ per g. of sample, andmonitoring the process by thin layer chromatography on Merck 0.25 mm.Kieselgel 60° F. 254 plates (Art. 5715), flash chromatography wasperformed in Merck Kieselgel (Art 9385); these materials were obtainedfrom E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) NMR spectra were normally determined at 90 MHz in CDCl₃ usingtetramethylsilane (TMS) as an internal standard, and expressed aschemical shifts (delta values) relative to TMS using the followingabbreviations for designation of major peaks: s, singlet; m, multiplet;t, triplet; br, broad; d,doublet.

When a single chemical shift value is given for a multiplet (m) thiscorresponds to the centre point of the signals making up the multiplet;

(vi) all end-products were isolated as racemates, and

(vii) those compounds of formula I wherein A is vinylene may contain3-5% by weight of the E-stereoisomeric form.

EXAMPLE 1

(2,2-Dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde (2.0 g.) wasadded under argon with stirring and ice-cooling to a solution of theylid prepared from (4-carboxybutyl)triphenylphosphonium bromide (11.25g.) and dimsyl sodium (5.4 g.) in dry dimethyl sulphoxide (150 ml.) andthe mixture was stirred overnight. Cautious addition of water (200 ml.)followed by extraction with ether (3×150 ml.) removed the bulk ofneutral material; acidification of the aqueous layer to pH 5-6 withaqueous oxalic acid followed by extraction with ether, drying (Na₂ SO₄)and evaporation, gave the crude product as a yellow oil. Columnchromatography, eluting with toluene/ethyl acetate/acetic acid (80:20:2v/v) gave 5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoicacid as an oil (1.8 g.) which solidified on standing to give material ofm.p. 76°-78° C.; NMR :1.55 (6H,s), 1.3-2.6 (9H,m), 3.7-4.3 (2H,m),5.1-5.5 (3H,m), 7.3 (5H, br s) and 9.59 (1H,s)ppm.

The starting material was obtained as follows:

A solution of ethyl 2-allyl-3-oxo-3-phenyl propionate * (10 g.) in drytetrahydrofuran (20 ml.) was added over 5 minutes to a suspension oflithium aluminium hydride (2 g.) in tetrahydrofuran (130 ml.) withstirring at -78° C. under argon. The mixture was allowed to warm to roomtemperature, stirred for 6 hours and was then treated with ethyl acetate(25 ml.) and saturated aqueous ammonium chloride solution (100 ml.).Filtration, extraction of the aqueous phase with ether (3×150 ml.),drying the ether layer (Na₂ SO₄) and evaporation gave a pale brown oil(10 g.). Column chromatography, eluting with chloroform/ethyl acetate(9:1 v/v) gave 2-allyl-1-phenyl-1,3-propanediol as a colourless oil (5.4g.); NMR: 1.6-2.2 (3H,m), 3.0 (1 H,s), and 7.3 (5H,br s).

A solution of 2-allyl-1-phenyl-1,3-propanediol (5.4 g.) in2,2-dimethoxypropane (250 ml.) was treated with p-toluenesulphonic acid(25 mg.) and allowed to stand overnight at room temperature. Addition oftriethylamine (5 drops) followed by evaporation gave a brown oil whichon flash column chromatography, (silica 30:1 per g. sample weight),eluting with toluene/hexane (1:1 v/v) gave(4,5-cis)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane as a colourless oil(2.1 g.) which solidified on standing to give material of m.p. 41°-43°C.; NMR: 1.55 (6H,s), 1.2-1.6 (3H,m), 3.8-4.2 (2H,m), 4.8-5.9 (3H,m),5.2 (1H,d, J=2.7 Hz) and 7.3 (5H, br s) ppm. and(4,5-trans)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane as a colourlessoil (1.8 g.) which solidified on standing to give material of m.p.31°-34° C.; NMR: 1.4 (3H,s), 1.5 (3H,s), 1.3-2.2 (3H,m), 3.5-4.0 (2H,m),4.5 (1H,d,J=10 Hz), 4.7-5.8 (3H,m) and 7.3 (5H,br s) ppm. Ozone waspassed through a solution of(4,5-cis)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane (2.1 g.) inmethylene chloride (200 ml.) at -78° C. until a permanent blue colourdeveloped. The solution was flushed with argon until colourless. Asolution of triphenylphosphine (2.1 g.) in dichloromethane (40 ml.) wasadded and the mixture was allowed to warm to room temperature.Evaporation followed by column chromatography, eluting withchloroform/ethyl acetate (19:1 v/v) gave(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde as a white solid(2.0 g.), m.p. 67°-69° C.; NMR: 1.55 (6H,s), 2.0-3.1 (3H,m), 3.7-4.4(2H,m), 5.2 (1H,d,J=2.0Hz) and 7.3 (5H,br s) ppm.

EXAMPLE 2

Diazomethane was distilled into a solution of5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)-heptenoic acid (320mg.) in dry ether (10 ml.) with ice-cooling until a yellow-green colourpersisted in the mixture. A solution of acetic acid in ether (10% v/v)was added until effervescence ceased. The mixture was concentrated,diluted with tetrachloromethane (20 ml.), decolourised with activatedcharcoal at room temperature and evaporated to give methyl5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoate as acolourless oil (300 mg.); NMR: 1.5 (6H,s), 1.4-2.4 (9H,m), 3.65 (3H,s),3.7-4.3 (2H,m), 5.2 (3H,m) and 7.3 (5H,s) ppm; m/e 332 (M⁺).

EXAMPLE 3

In a similar manner to Example 1, except that(4-carboxypentyl)triphenylphosphonium bromide was used instead of(4-carboxybutyl)triphenylphosphonium bromide, there was obtained6(Z)-8-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)octenoic acid as acolourless oil (2.2 g.); NMR: 1.5 (6H,s), 1.2-3.5 (11H,m), 3.7-4.3(2H,m) and 7.3 (5H,m) ppm; m/e 404[M⁺ +(CH₃)₃ Si].

EXAMPLE 4

In a similar manner to Example 1, but starting from(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde, there wasobtained 5(Z)-7-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acidas a colourless oil in 45% yield; NMR: 0.7-1.2 (6H,m), 1.3-2.6 (13H,m),3.7-4.3 (2H,m), 5.1-5.5 (3H,m) and 7.3 (5H, br s) ppm; m/e: 347 (M⁺ +H)and 317 (M⁺ -C₂ H₅).

The starting material was obtained as follows:

A solution of (4,5-cis)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane (20g.) in tetrahydrofuran (400 ml.) was treated with a solution ofhydrochloric acid (2M, 10 ml.) in water (100 ml.) and the resultingsolution was heated under reflux for 3 hours. The mixture wasevaporated. The brown oil obtained was dissolved in ethyl acetate (200ml.). The solution was washed with water (3×10 ml.), dried (Na₂ SO₄) andevaporated to give crude erythro-2-allyl-1-phenyl-1,3-propanediol (17g.) as a colourless oil which was used without further purification.

A solution of crude erythro-2-allyl-1-phenyl-1,3-propanediol (17 g.) intoluene (200 ml.) containing 3-pentanone (10 g.) and p-toluenesulphonicacid (50 mg.) was heated under reflux for 4 hours using a Dean and Starkapparatus for removal of water. The reaction mixture was diluted withtoluene (100 ml.), washed with aqueous sodium hydroxide (2M, 50 ml.) andthen water (100 ml.), dried (Na₂ SO₄) and evaporated to give a brown oilwhich on column chromatography, eluting with toluene, gave(4,5-cis)-5-allyl-2,2-diethyl-4-phenyl-1,3-dioxane (5.8 g.) as acolourless oil; NMR: 0.7-1.2 (6H,m), 1.4-2.6 (7H,m), 3.7-4.3 (2H,m),4.7-5.9 (3H,m), 5.2 (1H,d, J=3 Hz) and 7.3 (5H,m)ppm.

Ozone was passed through a solution of(4,5-cis)-5-allyl-2,2-diethyl-4-phenyl-1,3-dioxane (5.8 g.) indichloromethane (600 ml.) at -78° C. until a permanent blue colourdeveloped. The solution was flushed with argon until colourless. Asolution of triphenyl-phosphine (7.5 g.) in dichloromethane (150 ml.)was then added and the mixture was stirred overnight at -20° C. and for3 hours at room temperature. The mixture was evaporated and the residuewas purified by column chromatography, eluting with chloroform/ethylacetate (19:1, v/v) to give(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde as a colourlessoil (4.3 g.); NMR: 0.7-1.2 (6H,m), 1.6-3.0 (7H,m), 3.6-4.4 (2H,m), 5.2(1H,d, J=2.4 Hz), 7.3 (5H, br s) and 9.5 (1H,s) ppm.

EXAMPLE 5

In a similar manner to Example 1, but starting from[2,2-dimethyl-4-(2-methylphenyl)-1,3-dioxan-cis-5-yl]acetaldehyde, therewas obtained5(Z)-7-[2,2-dimethyl-4-(2-methylphenyl)-1,3-dioxan-cis-5-yl]-heptenoicacid as a white solid (0.69 g.); m.p. 72°-75° C.; NMR: 1.55 (6H,s), 2.3(3H,s), 1.3-2.7 (9H,m), 3.7-4.3 (2H,m), 5.0-5.6 (3H,m) and 7.1-7.6(4H,m)ppm; m/e: 333 [M⁺ +H].

The starting material was obtained as an oil using an analogousprocedure to that described in Example 1; NMR: 1.5 (3H,s), 1.6 (3H,s),1.8-2.9 (3H,m), 2.4 (3H,s), 3.6-4.2 (2H,m), 4.9 (1H,d, J=9 Hz), 7.1-7.6(4H,m) and 9.45 (1H,s) ppm; starting from ethyl2-allyl-3-(2-methylphenyl)-3-oxopropionate, itself obtained as an oilusing a similar procedure to that of C. S. Marvel and F. D. Hager,Organic Syntheses Coll. Vol. I, p. 248.

The following intermediates analogous to those in Example 1 wereisolated:

(a) 2-allyl-1-(2-methylphenyl)-1,3-propanediol as a colourless oil; NMR:1.6-2.6 (3H,m), 2.3 (3H,s), 3.7 (2H,d), 4.8-6.0 (4H,m) and 7.0-7.7(4H,m) ppm;

(b) (4,5-cis)-5-allyl-2,2-dimethyl-4-(2-methylphenyl)-1,3-dioxane as anoil; NMR : 1.3-2.6 (3H,m), 1.55 (6H,s), 2.3 (3H,s), 3.7-4.3 (2H,m),4.8-5.8 (3H,m), 5.3 (1H,d, J=2.7 Hz) and 7.0-7.7 (4H,m) ppm.

EXAMPLE 6

In a similar manner to Example 1, but starting from(4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde, there was obtained:5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)-heptenoic acid as a colourless oilin 61% yield, which solidified to give material of m.p. 42°-46° C.; NMR:1.5-2.6 (9H,m), 3.7-4.3 (2H,m), 4.8-5.6 (5H,m) and 7.3 5H,br s) ppm; m/e290 [M⁺ ].

The starting material was obtained as follows:

A solution of crude erythro-2-allyl-3-phenyl-1,3-propanediol (50 g.) intoluene (100 ml.) containing dimethoxymethane (5 ml.) andp-toluenesulphonic acid (25 mg.) was heated under reflux for 2 hours.Further dimethoxymethane (2 ml.) was added and heating was continued for1 hour. The reaction mixture was cooled and washed with water (2×50ml.). The organic phase was dried (Na₂ SO₄) and evaporated. The brownoil obtained was purified by column chromatography, eluting with tolueneto give (4,5-cis)-5-allyl-4-phenyl-1,3-dioxane (A) (520 mg.) as acolourless oil; NMR 1.5-2.6 (3H,m), 3.7-4.3 (2H,m), 4.8-5.9 (5H,m), 5.3(1H,d, J=6 Hz) and 7.3 (5H, br s) ppm.

A solution of A (500 mg.) in t-butyl alcohol (5 ml.) was added to asolution containing sodium periodate (1.2 g.), water (5 ml.), t-butylalcohol (35 ml.) and osmium tetroxide (5 mg.). The mixture was stirredfor 3 hours. Water (100 ml.) was added to dissolve the precipitate andthe aqueous solution was extracted with toluene (3×50 ml.). The extractswere dried (Na₂ SO₄), evaporated and gave, after column chromatography,eluting with chloroform/ethyl acetate (19:1 v/v),(4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde as a colourless oil (200mg.); NMR: 2.1-3.2 (3H,m), 4.1 (2H,m), 4.9-5.4 (3H,m), 7.3 (5H, br s)and 9.6 (1H,br s)ppm.

EXAMPLE 7

A solution of3-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)propionaldehyde (500 mg.)in dry dimethyl sulphoxide (5 ml.) was added under argon withice-cooling to a stirred solution of the ylid prepared from(4-carboxypropyl)triphenylphosphonium bromide (2.4 g.) and dimsyl sodium(1.2 g.) in dry dimethyl sulphoxide (20 ml.). The mixture was stirredfor 18 hours. Water (50 ml.) was added and the aqueous mixture wasextracted with ether (3×50 ml.) to remove the bulk of the neutralmaterial. The aqueous layer was acidified to pH 5-6 (2M hydrochloricacid) and extracted with ether (4×50 ml.). The combined extracts weredried (Na₂ SO₄) and evaporated. The residual yellow oil was purified bycolumn chromatography eluting with toluene/ethyl acetate/acetic acid(80/20/2 v/v) to give4(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)-heptenoic acid as anoil (300 mg.); NMR: 1.5(6H,s), 1.3-2.6 (9H,m), 3.7-4.3 (2H,m), 4.9-5.4(3H,m) and 7.3 (5H,br s)ppm; m/e: 191, 107 and 91.

The starting material was obtained as follows:

A solution of borane in tetrahydrofuran (1M,11 ml.) was added over 10minutes to an ice-cooled, stirred solution of(4,5-cis)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane (2.32 g.) in drytetrahydrofuran (50 ml.) under argon. Stirring was continued for 30minutes and the mixture was treated sequentially with aqueous sodiumhydroxide (1M, 20 ml.) and hydrogen peroxide (30% w/v; 5 ml.). After afurther 30 minutes, saturated brine (100 ml.) was added and the mixturewas extracted with ethyl acetate (3×70 ml.). The extracts were dried(Na₂ SO₄) and evaporated to give3-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)-1-propanol (B) (2.6 g.) asa colourless oil which was used without further purification. Asuspension of pyridinium chlorochromate (1.62 g.) in dichloromethane (25ml.) was treated with a solution of B (1.25 g.) in dichloromethane (10ml.). The mixture was stirred for 40 minutes. Ether (100 ml.) was thenadded and the solution was poured through a short column containingactivated magnesium silicate (25 g., 60-100 Mesh). The column wasthoroughly eluted with ether and the eluate was evaporated. The residualoil was purified by column chromatography, eluting with chloroform/ethylacetate (9:1 v/v), to give3-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)propionaldehyde as acolourless oil (550 mg.); NMR: 1.55 (6H,s), 1.2-2.3 (5H,m), 3.7-4.3(2H,m), 5.2 (1H, br s), 7.3 (5H, br s) and 9.55 (1H,s) ppm.

EXAMPLE 8

A solution containingerythro-5(Z)-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid (140 mg.),p-toluenesulphonic acid (5 mg.) and phenylacetaldehyde dimethyl acetal(125 μl.) in dry tetrahydrofuran (5 ml.) was heated at 60°-65° C. for 24hours. The cooled reaction mixture was evaporated and the residuediluted with ether (10 ml.). The solution obtained was washed with water(5 ml.), saturated aqueous sodium bicarbonate (5 ml.), water (5 ml.) andsaturated brine (5 ml.) then dried (MgSO₄) and evaporated to give ayellow oil, which was purified by column chromatography, eluting withdichloromethane/methanol (19:1 v/v), to give5(Z)-7-(2-benzyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid as a paleyellow oil (100 mg.); NMR:1.3-2.6 (9H,m), 3.0 (2H,d), 3.7-4.3 (2H,m),4.8-5.5 (4H,m) and 7.3 (5H,br s) ppm; microanalysis, found: C, 75.7;H,7.6%; calculated: C, 75.79;H, 7.37%.

The starting material was obtained as follows:

A solution containing5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (5.2g.), water (20 ml.) and aqueous hydrochloric acid (2M, 3 ml.) intetrahydrofuran (180 ml.) was heated at 60°-70° C. for hours and thenevaporated. The residue obtained was diluted with ethyl acetate (100ml.), washed with water (3×100 ml.), dried (Na₂ SO₄) and evaporated togive crude erythro-5(Z)-9-hydroxy-8-hydroxymethyl-9-phenyl-5-nonenoicacid as a colourless oil (4.5 g.) which was used without furtherpurification.

EXAMPLE 9

Using a similar procedure to that in Example 8, but starting fromcyclohexanone diethyl acetal, there was obtained5(Z)-7-(4'-phenyl-[cyclohexanespiro-2'-1,3-dioxan]-cis-5,'-yl)heptenoicacid as a colourless oil, which solidified on standing to give materialof m.p. 76°-79° C.; NMR: 1.3-2.7 (19H,m 3.7-4.3 (2H,m), 5.2-5.6 (3H,m)and 7.3 (5H, br s) ppm; m/e: 358 (M⁺).

EXAMPLES 10-22

Using a similar procedure to that described in Example 1, but startingfrom the appropriate aldehyde of formula II (n=1) and the ylid from(4-carboxybutyl)triphenylphosphonium bromide, the following compounds ofthe formula Ib (Ra═Rb═methyl)

    ______________________________________                                             Ring             NMR        Mass    Base/                                     B       m.p.     (Ring B-1H)                                                                              Spectrum                                                                              Yield                                Ex.  Subs.   (°C.)                                                                           ppm        m/e     (%)                                  ______________________________________                                        10   2-Cl    58-62    7.28 (3H,m)                                                                              (M + H) D/63                                                       7.75 (1H,m)                                                                              353                                          11   2-F     71-74    7.07 (3H,m)                                                                              (M + H) D/35                                                       7.5 (1H,m) 337                                          12   2-CF.sub.3                                                                            oil      7.55 (4H,m)                                                                              (M + H) D/33                                                                  387                                          13   2-OMe   112-114  7.1 (4H,m) (M + H) T/59                                                       3.7 (3H,s;OMe)                                                                           349                                          14   2-Pr.sup.i                                                                            oil      7.2 (3H,m) (M + H) D/32                                                       7.3 (1H,m) 361                                                                3.03 (1H,m)                                                                   1.21 (6H,d)                                             15   2-Et    oil      7.17 (3H,m)                                                                              (M + H) T/81                                                       7.46 (1H,m)                                                                              347                                                                2.57 (2H,q)                                                                   1.16 (3H,t)                                             16   2,6-F.sub.2                                                                           oil      6.86 (3H,m)                                                                              (M + H) T/44                                                       7.19 (1H,m)                                                                              355                                          17   3-F     50-53    6.8-7.5 (4H,m)                                                                           (M--Me) D/27                                                                  321.150                                      18   4-Me    94-99    7.1-7.28 (4H,m)                                                                          (M + H) T/80                                                       2.3 (3H,s; CH.sub.3)                                                                     333                                          19   3-CF.sub.3                                                                            55-58    7.4-7.58 (4H,m)                                                                          (M--Me) T/93                                                                  386.1698                                     20   3-Cl    oil      7.0-7.3 (4H,m)                                                                           (M--Me) T/60                                                                  337.120                                      21   4-NO.sub.2                                                                            oil      7.4-8.4 (4H,m)                                                                           (M)     B/69                                                                  363.1671                                     22   4-F     74-77    6.9-7.4 (4H,m)                                                                           (M + H) T/75                                                                  337                                          ______________________________________                                         Notes:                                                                        (i) NMR: determined at 90 MHz in CDCl.sub.3 ; all the spectra contained       the following additional signals: 1.55 (6H,s,CH.sub.3), 1.3-2.6 (9H,m;        CH.sub.2, CH), 3.7-4.3 (2H,m,OCH.sub.2) and 5.1-5.5 (3H,m; CH═CH,         OCHPh).                                                                       (ii) Bases used for generation of ylid: D = dimsyl sodium + dimethyl          sulphoxide; T = potassium tbutoxide + tetrahydrofuran; B = butyl lithium      tetrahydrofuran. The solvent used for the generation of the ylid was used     for the reaction between the ylid and the aldehyde of formula II.             (iii) For Ex. 21, the ylid was added to a solution of the aldehyde in         tetrahydrofuran at -70° C.                                        

The necessary starting aldehydes of formula II (Ra═Rb═CH₃, n=1) wereobtained in yields of 56-95% from the corresponding derivatives offormula VII (Ra═Rb═methyl) in an analogous manner to that described inExample 1 starting from the appropriate ethyl 2-allyl-3-(substitutedphenyl)-3-oxopropionate of formula V (R=ethyl). The aldehydes had thefollowing properties:

    ______________________________________                                             Ring                 IR                                                       B        NMR         (--CHO)                                                                              Physical                                     No.  Subs     (Ring B-.sup.1 H)                                                                         cm.sup.-1                                                                            Form                                         ______________________________________                                        10a  2-Cl     7.25 (3H,m) 1720   oil                                                        7.55 (1H,m)                                                     11a  2-F      **          1720   oil                                          12a  2-CF.sub.3                                                                             **          1720   oil                                          13a  2-OMe    **          1720   oil                                          14a  2-Pr.sup.i                                                                             **          1720   oil                                          15a  2-Et     **          1720   oil                                          16a  2,6-F.sub.2                                                                            7.12 (3H,m) 1720   solid                                                                         m.p. 46-47° C.                        17a  3-F      **          1720   oil                                          18a  4-Me     **          1720   oil                                          19a  3-CF.sub.3                                                                             **          1720   oil                                          20a  3-Cl     **          1720   oil                                          21a  4-NO.sub.2                                                                             7.4-8.4 (4H,m)                                                                            1715   oil                                          22a  4-F      **          1720   oil                                          ______________________________________                                         Notes:                                                                        IR: Infrared spectra were generally determined as liquid films on rocksal     plates.                                                                       NMR: All the spectra contained the following additional signals: 1.55         (6H,s,CH.sub.3), 2.0-3.1 (3H,m,C--H--C--H.sub.2 CHO), 3.7 (2H, m,             OCH.sub.2) and 5.2 (1H, d, J = 2 Hz, OCHPh).                                  **: NMR spectrum not determined; material essentially pure by thin layer      chromatography (TLC) (SiO.sub.2 :1:9 v/v ethyl acetate/chloroform).      

The following intermediate(4,5-cis)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxanes of formula VII(Ra═Rb═Methyl) were isolated (any isometric(4,5-trans)-5-allyl-2,2-dimethyl-4-phenyl-1,3-dioxane being removed bychromatography):

    ______________________________________                                              Ring                                                                          B       NMR           Yield Physical                                    No.   Subs    (Ring B-.sup.1 H)                                                                           (%)   Form                                        ______________________________________                                        10b   2-Cl    7.27 (3H,m)   38    oil                                                       7.61 (1H,m)                                                     11b   2-F     7.07 (3H,m)   24    oil                                                       7.49 (1H,m)                                                     12b   2-CF.sub.3                                                                            7.52 (4H,m)   10    oil                                         13b   2-OMe   7.11 (4H,m)   56    Solid                                                     3.82 (3H,s,OMe)     m.p. 77-79° C.                       14b   2-Pr.sup.i            21    oil                                         15b   2-Et    7.17 (3H,m)   42    oil                                                       7.42 (1H,m)                                                                   1.21 (3H,m,Me)                                                  16b   2,6-F.sub.2                                                                           6.95 (2H,m)   80    oil                                                       7.31 (1H,m)                                                     17b   3-F     6.8-7.45 (4H,m)                                                                             28    oil                                         18b   4-Me    7.0-7.25 (4H,m)                                                                             21    oil                                                       2.3 (3H,s,CH.sub.3)                                             19b   3-CF.sub.3                                                                            7.4-7.65 (4H,m)                                                                             30    oil                                         20b   3-Cl    7.1-7.35 (4H,m)                                                                             26    oil                                         21b   4-NO.sub.2                                                                            7.4-8.4 (4H,m)                                                                              33    oil                                         22b   4-F     6.9-7.4 (4H,m)                                                                              39    oil                                         ______________________________________                                         Notes:                                                                        NMR: the following NMR signals were common to all the compounds: 1.55         (6H,s), 1.2-1.6 (3H,m), 3.8-4.2 (2H,m), 4.8-5.9 (3H,m) and 5.2 (1H,d, J =     2.7 Hz).                                                                 

Yields: yields quoted are from the 2-allyl-3-(substitutedphenyl)-3-oxo-propionate of formula V (Ra═Rb═methyl, R═ethyl). Thatquoted for No. 16b is from essentially pureerythro-2-allyl-1-(2,6-difluorophenyl)-1,3-propanediol and that quotedfor No. 13b is from 4:1 erythro- tothreo-2-allyl-1-(2-methoxyphenyl)-1,3-propanediol.

The 5-allyl-1,3-dioxane derivatives of formula VII (Ra═Rb═methyl) werethemselves obtained by cyclisation of the erythro-form of theappropriate 2-allyl-1-(substituted phenyl)-1,3-propanediol of formulaVIa (Ra═Rb═methyl) in the presence of 2,2-dimethoxypropane by analogywith the procedure in Example 1. The required erythro-diols of formulaVIa were generally obtained, together with the corresponding threo-diolsof formula VIb, as oils by lithium aluminium hydride or lithiumborohydride reduction of the ethyl 2-allyl-3-(substitutedphenyl)-3-oxopropionate of formula V and were used without specialpurification or characterisation.

Alternatively the erythro- diol of the formula VIa may be obtainedessentially free of the threo-isomer VIb by a two stage reductionprocedure using first zinc borohydride followed by lithium aluminiumhydride. The latter procedure is illustrated by the production oferythro-2-allyl-1-(2,6-difluorophenyl)-1,3-propanediol:

(a) A solution of anhydrous zinc chloride (1.7 g.) in anhydrous ether(20 ml.) was added to a stirred suspension of sodium borohydride (1.1g.) in anhydrous ether (40 ml.) and the mixture stirred for 18 hours.Solid material was removed by filtration. A solution of ethyl2-allyl-3-(2,6-difluorophenyl)-3-oxopropionate (1.4 g.) in anhydrousether (10 ml.) was then added over 5 minutes to the filtrate which hadbeen cooled to 0° C. The subsequent mixture was stirred at 0° C. for 45minutes. 2M Hydrochloric acid was then added until gas evolution ceased.The organic phase was separated, washed with saturated brine, dried(MgSO₄) and evaporated. The oil (1.3 g.) obtained was purified by flashcolumn chromatography on silica (40 g.) using 15% v/v ethyl acetate inpetroleum ether (b.p. 60°-80° C.) as eluent to give ethylerythro-2-allyl-3-(2,6-difluorophenyl)-3-hydroxypropionate (A) (400 mg.)as an oil; NMR: 1.02 (3H,t), 2.58 (3H,m), 3.12 (1H,m), 3.90 (2H,q), 5.13(3H,m), 5.83 (1H,m), 6.83 (2H,m) and 7 24 (1H,m) ppm.

(b) A solution of the ester (A) (340 mg.) in anhydrous ether (10 ml.)was added under nitrogen over 3 minutes to a stirred suspension oflithium aluminium hydride (120 mg.) in anhydrous ether (30 ml.) at 0° C.The mixture was heated under reflux for 30 minutes and cooled byice-water. Ethyl acetate (2 ml.) in anhydrous ether (10 ml.) was thenadded, followed by saturated ammonium chloride solution (25 ml.). Themixture obtained was separated by filtration. The organic phase waswashed with saturated brine, dried (MgSO₄) and evaporated to giveerythro-2-allyl-1-(2,6-difluorophenyl)-1,3-propanediol as an oil (252mg.); NMR 2.30 (5H,m), 3.60 (2H,d), 5.18 (3H,m), 5.9 (1H,m), 6.95 (2H,m)and 7.30 (1H,m) ppm.

The lithium borohydride procedure is illustrated by the production of2-allyl-1-(2ethylphenyl)-1,3-propanediol:

A solution of 2-allyl-3-(2-ethylphenyl)-3-oxopropionate (7.3 g.) in drytetrahydrofuran (THF) (40 ml.) was added during 10 minutes to a stirredsuspension of lithium borohydride (1.32 g.) in dry THF (40 ml.) at 0° C.under a nitrogen atmosphere. The mixture was then stirred at roomtemperature for 18 hours, cooled to 0°-5° C. and water (40 ml.) added.The aqueous mixture was acidified to pH 2 (concentrated hydrochloricacid) and extracted with ethyl acetate (3×120 ml.). The combinedextracts were washed with saturated brine, dried (MgSO₄) and evaporated.The residual oil (6.1 g.) was purified by chromatography on silica (180g.) using 3:7 v/v ethyl acetate/petroleum ether (b.p.60°-80° C.) to give2-allyl-1-(2-ethylphenyl)propane-1,3-diol (containing approximately 4:1erythro- to threo-forms) as an oil (4.0 g.); NMR: 1.19 (3H,m), 2.04(5H,m), 2.59 (2H,m), 3.76 (2H,m), 5.02 (3H,m), 5.67 (1H,m), 7.17 (3H,m),and 7.47 (1H,m)ppm.

The starting ethyl 2-allyl-3-(substituted phenyl)-3-oxopropionates offormula V (R=ethyl) may be obtained as oils by allylation of theappropriate 3-(substituted phenyl)-3-oxopropionate using the generalprocedure of Marvel and Hager. Examples of esters of formula V obtainedin this way are those wherein benzene ring B is 2-chloro-, 3-chloro,3-fluoro-, 2-methoxy-, 2-isopropyl-, 2-trifluoromethyl,3-trifluoromethyl- and 4-methyl-phenyl. The necessary starting3-oxopropionates were made using one of the following well known,standard procedures:.

(a) reaction of the appropriate substituted benzoyl chloride witht-butyl ethyl malonate and magnesium ethoxide to give the correspondingt-butyl ethyl 2-(substituted benzoyl)malonate which is then thermolysedat 100° C. in vacuo in the presence of p-toluenesulphonic acid (e.g.those 3-oxopropionates wherein benzene ring B is 2-chloro-,2-methoxy-,2-isopropyl- and 2-trifluoromethyl-phenyl); or

(b) reaction of the appropriate substituted benzoyl chloride with thedilithium salt of monoethyl malonate (obtained from two molecularequivalents of butyl lithium in hexane at -70° C.) at -65° C., followedby acidification with concomitant decarboxylation at room temperature(e.g. those 3-oxopropionates wherein benzene ring B is 3-fluoro-,3-chloro-, 3-trifluoromethyl- and 4-methyl-phenyl).

Alternatively, the starting 2-allyl-3-(substitutedphenyl)-3-oxopropionates of formula V (R=ethyl) may be obtained fromt-butyl ethyl malonate as illustrated below:

(a) Potassium carbonate (28.0 g.) was added to a stirred solution oft-butyl ethyl malonate (37.6 g.) in dry N,N-dimethylformamide (DMF) (100ml.). After 1 hour allyl bromide (34 ml.) was added. The mixture washeated at 70° C. for 66 hours, cooled to room temperature and dilutedwith water (900 ml.). The mixture obtained was extracted with ethylacetate (3×200 ml.). The extracts were dried (MgSO₄) and evaporated. Theoil obtained was purified by flash column chromatography eluting with1:15 v/v ethyl acetate/petroleum ether (b.p. 60°-80° C.) to give t-butylethyl 2-allylmalonate as a colourless oil (15.6 g.), b.p. 70°-72° C. at0.2 mmHg; NMR: 1.21 (3H,t), 1.42 (9H,s), 2.66 (2H,m), 3.28 (1H,m), 4.16(2H,q), 5.06 (2H,m) and 5.76 (1H,m) ppm.

(b) Sodium hydride (2.8 g., 50% w/w dispersion in mineral oil) was addedover 15 minutes to an ice cooled solution of t-butyl ethyl2-allylmalonate (13.4 g.) in dry DMF (120 ml.) under nitrogen. Themixture was stirred at room temperature for 45 minutes and cooled to 0°C. 2-Ethylbenzoyl chloride (10.1 g.) was added over 2 minutes and themixture stirred at room temperature for 18 hours. The DMF was evaporatedand the residue shaken with water (100 ml.) and ethyl acetate (200 ml.).The ethyl acetate phase was separated, washed with saturated brine,dried (MgSO₄) and evaporated. The oil obtained (21.8 g.) was purified byflash column chromatography on silica (650 g.) using toluene as eluantto give t-butyl ethyl 2-allyl-2-(2-ethylbenzoyl)malonate (14.3 g.) as anoil; NMR: 1.25 (15H,m), 2.7 (2H,q), 2.9 (2H,d), 4.12 (2H,q), 5.31(2H,m), 6.05 (1H,m) and 7.35 (4H,m) ppm.

(c) A mixture of t-butyl ethyl 2-allyl-2-(2-ethylbenzoyl)malonate (14.3g.), acetic anhydride (4 ml.) and p-toluenesulphonic acid (100 mg.) inacetic acid (200 ml.) was heated at 140° C. under nitrogen for 75minutes and then evaporated. The residue was shaken with a mixture ofsaturated sodium bicarbonate solution (100 ml.) and ethyl acetate (100ml.). The organic phase was dried (MgSO₄) and evaporated. The oilobtained (9.3 g.) was purified by flash column chromatography (280 g.)using toluene as eluant to give ethyl2-allyl-3-(2-ethylphenyl)-3-oxopropionate (7.4 g.) as a pale yellow oil;NMR: 1.19 (6H,m), 2.74 (4H,m), 4.15 (3H,m), 5.05 (2H,m), 5.79 (1H,m),7.30 (3H,m) and 7.61 (1H,m) ppm.

An analogous procedure to (a)-(c) above was used in addition for thepreparation of:

(i) ethyl 2-allyl-3-(2,6-difluorophenyl)-3-oxopropionate, obtained as anoil. NMR: 1.2 (3H,t), 2.70 (2H,m), 4.17 (3H,m), 4.92 (2H,m), 5.73(1H,m), 6.95 (2H,m) and 7.26 (1H,m) ppm; and

(ii) ethyl 2-allyl-3-(2-fluorophenyl)-3-oxopropionate, obtained as anoil; NMR: 1.23 (3H,t), 2.67 (2H,m), 4.20 (3H,m), 5.04 (2H,m), 5.83(1H,m), 7.09 (2H,m), 7.37 (1H,m) and 7.73 (1H,m) ppm.

Characteristic NMR data for other representative2-allyl-3-oxopropionates of formula V (R=ethyl) obtained as oils bydirect sodium ethoxide allylation of the corresponding ethyl3-(substituted phenyl)-3-oxopropionate are as follows:

(i) ethyl 2-allyl-3-(2-trifluoromethylphenyl)-3-oxopropionate; NMR: 1.21(3H,m), 2.75 (2H,m), 4.14 (3H,m), 5.04 (2H,m), 5.90 (1H,m) and 7.59(4H,m) ppm;

(ii) ethyl 2-allyl-3-(2-chlorophenyl)-3-oxopropionate; NMR: 1.20 (3H,m),2.71 (2H,m), 4.18 (3H,m), 4.93 (2H,m), 5.73 (1H,m) and 7.34 (4H,m) ppm;and

(iii) ethyl 2-allyl-3-(2-methoxyphenyl)-3-oxopropionate; NMR: 1.17(3H,m), 2.69 (2H,m), 4.10 (6H,m), 5.00 (2H,m), 5.81 (1H,m), 6.95 (2H,m),7.38 (1H,m) and 7.51 (1H,m) ppm.

EXAMPLES 23-24

Using a similar procedure to that described in Example 1 the followingacids of formula I were obtained:

(EXAMPLE 23)

5(Z)-7-([2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-5-yl)heptenoic acid, asa solid in 55% yield, m.p. 31°-32° C.; NMR: 1.0-2.4 (12H,m), 3.7-4.3(2H,m), 4.7-5.0 (2H,m), 5.1-5.5 (2H,m) and 7.1-7.5 (5H,m) ppm; startingfrom ([2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-5-yl)acetaldehyde andusing potassium t-butoxide and tetrahydrofuran instead of dimsyl sodiumand dimethyl sulphoxide;

(EXAMPLE 24)

5(Z)-7-(2,2-dipropyl-4-phenyl-1,3-dioxan-cis-5-yl)beptenoic acid as anoil in 60% yield; NMR: 0.8-2.8 (23H,m), 3.6-4.3 (2H,m), 5.0-5.6 (3H,m),7.1-7.6 (5H,m) and 9.3 (1H,br s) ppm, starting from(2,2-dipropyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde.

The starting acetaldehyde for 23 was obtained as an oil [NMR: 1.45(3H,d, J=5.0 Hz), 2.1-3.1 (3H,m). 4.05 (2H,s), 4.7-5.1 (2H,m), 7.1-7.5(5H,m) and 9.55 (1H,s) ppm] in 89% yield by oxidation of(2,4,5-cis-5-allyl-2-methyl-4-phenyl-1,3-dioxane, itself obtained as anoil [NMR: 1.45 (3H,d, J=5.0 Hz), 1.5-2.6 (3H,m), 3.7-4.3 (2H,m), 4.8-5.1(4H,m), 5.3-5.8 (1H,m) and 7.1-7.5 (5H,m) ppm] in 79% yield bycyclisation of the erythroform of 2-allyl-1-phenyl-1,3-propanediol withacetaldehyde, using analogous procedures to those described for Example1.

The starting acetaldehyde for 24 was obtained as an oil in 95% yield byoxidaton of (4,5-cis)-5-allyl-2,2-dipropyl-4-phenyl-1,3-dioxane using asimilar procedure to that described in Example 4. The latter dioxane wasitself obtained as an oil; NMR: 0.7-2.7 (17H,m), 3.7-4.2 (2H,m), 4.7-5.8(4H,m) and 7.0-7.4 (5H,m) ppm, in 42% yield by reaction oferythro-2-allyl-1-phenyl-1,3-propanediol with 3-pentanone using asimilar procedure to that described for the analogous compound inExample 4.

EXAMPLES 25-29

A mixture of cyclopentanone (0.165 ml.),erythro-5(Z)-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid (0.52 g.),triethyl orthoformate (0.4 ml.) and p-toluenesulphonic acid (5 mg.) wasstirred for 3 hours. Ether (25 ml.) was then added and the solution wasextracted with a solution of potassium hydroxide (0.21 g.) in water (10ml.). The basic extract was washed with ether (10 ml.) and thenacidified to pH 4 (2M hydrochloric acid). The resultant emulsion wasextracted with ether (2×30 ml.). The combined extracts were washed withwater (3×20 ml.) and saturated brine (20 ml.), then dried (MgSO₄) andevaporated. The yellow oil obtained was purified by flash columnchromatography, using 80:20:2 v/v toluene/ethyl acetate/acetic acid togive5(Z)-7-(4'-phenyl-[cyclopentanespiro-2'-1,3-dioxan]-cis-5-yl)heptenoicacid (Example 25) as a colourless oil (400 mg.); NMR: 1.4-2.5 (17H,m),3.7-4.2 (2H,m), 5.1 (1H,d, J=2 Hz), 5.2-5.5 (2H,m) and 7.1-7.5 (5H,m);m/e: 344 (M⁺)

Using a similar procedure, but starting from the appropriate ketone, thefollowing acids of formula Ib wherein benzene ring B is unsubstitutedwere obtained:

(EXAMPLE 26)

Ra+Rb=trimethylene; as an oil in 37% yield; NMR: 1.3-2.7 (15H,m),3.7-4.1 (2H,m), 5.0 (1H,d,J=2 Hz), 5.1-5.5 (2H,m), 7.1-7.4 (5H,m) and9.0 (1H,br s) ppm; m/e: 330 M⁺.

(EXAMPLE 27)

Ra+Rb=hexamethylene; as an oil in 42% yield; NMR: 1.2-2.6 (21H,m),3.6-4.3 (2H,m), 5.1-5.5 (3H,m) and 7.1-7.5 (5H,m) ppm; m/e:372 M⁺.

(EXAMPLE 28)

Ra=Rb=butyl; as an oil in 10% yield; NMR: 0.7-2.6 (27H,m), 3.7-4.2(2H,m), 5.1-5.4 (3H,m) and 7.1-7.4 (5H,m) ppm.

(EXAMPLE 29)

Ra=phenyl Rb=methyl; as an oil in 40% yield; NMR: 1.65 (3H,s), 7.0-7.6(10H,m) and 7.7-8.7 (1H,br s) ppm; m/e: 380 (M⁺).

EXAMPLES 30-32

Using a similar procedure to that described in Example 8 but replacingphenylacetaldehyde dimethyl acetal by:

(a) 1,1-dimethoxyheptane, there was obtained5(Z)-7-([2,4,5-cis]-2-hexyl-4-phenyl-1,3-dioxan-5-yl)heptenoic acid(Example 30) as a solid, m.p. 60°-62° C. in 74% yield; NMR: 0.9 (3H,t),1.1-2.6 (17H,m), 3.7-4.2 (2H,m), 2.7 (1H,t,J=4.0 Hz), 4.9 (1H,d,J=3.0Hz), 5.1-5.5 (2H,m) and 7.1-7.4 (5H,m) ppm; and

(b) 1,1-diethoxypropane, there was obtained5(Z)-7-([2,4,5-cis]-2-ethyl-4-phenyl-1,3-dioxan-5-yl)heptenoic acid(Example 31) as an oil in 63% yield; NMR: 1.0 (3H,m), 1.3-2.6 (11H,m),3.7-4.3 (2H,m), 4.7 (1H,t,J=5.0 Hz), 4.9 (1H,d, J=3.0 Hz), 5.1-5.5(2H,m), 7.1-7.4 (5H,m) and 8.2 (1H,br s) ppm.

Similarly, by using the procedure of Example 8 witherythro-5(Z)-9-hydroxy-8-hydroxymethyl-9-(2-methylphenyl)nonenoic acid(A) and 3,3-dimethoxypentane, there was obtained5(Z)-7-(2,2-diethyl-4-(2-methylphenyl)-1,3-dioxan-cis-5-yl)heptenoicacid (EXAMPLE 32) as an oil in 65% yield; NMR: 0.7-1.3 (6H,m), 1.4-2.6(13H,m), 2.13 (3H,s), 3.6-4.2 (2H,m), 4.9-5.4 (3H,m) and 7.0-7.6 (4H,m).

The necessary starting acid (A) was obtained as an oil in a similarmanner to the 9-phenyl analogue described for Example 8, but startingfrom5(Z)-7-[2,2-dimethyl-4-(2-methylphenyl)-1,3-dioxan-cis-5-yl]heptenoicacid; NMR: 1.1-2.5 (9H,m), 2.3 (3H,s), 3.8 (2H,d, J=5.0 Hz), 4.6-5.6(3H,m) and 7.0-7.7 (4H,m) ppm.

EXAMPLE 33

5(Z)-7-(2,2-Dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (191mg, 0.6 mM) was dissolved in dry toluene (10 ml.), and freshly-distilledbenzaldehyde (212 mg., 1.2 mM) and p-toluenesulphonic acid (3 mg.) wereadded. The mixture was heated at 100° C., with stirring, while beingprotected from the atmosphere (drying tube), for 1-2 hours until thinlayer chromatography (TLC) indicated completion of the reaction. Thecooled reaction mixture was purified by flash column chromatography onsilica (20 g.) eluting with 5% v/v methanol in methylene chloride. Therewas thus obtained5(Z)-7([2,4,5-cis]2,4-diphenyl1,3-dioxan-5-yl)heptenoic acid as aviscous oil (254 mg.); NMR: 1.4-2.8 (9H,m) 4.1-4.3 (2H,m), 5.1-5.5(3H,m), 5.75 (1H,s), 7.2-7.7

(10H,m) ppm; m/e: 366 (M⁺), 348 (M-H₂ O), 279 [M-(CH₂)₃.CO₂ H], 260(M-PhCHO).

EXAMPLES 34-64

Using a similar procedure to that described in Example 33 but replacingbenzaldehyde by the appropriate substituted aldehyde of the formulaRa.CHO, the following acids of formula Ib (benzene ring B isunsubstituted, Rb=H) were obtained in yields of 37-92% using either 10%v/v methanol in methylene chloride, 40% v/v acetone in methylenechloride, or 40:10:1 by (volume) toluene/ethyl acetate/acetic acid asthe eluant for the flash chromatography.

    ______________________________________                                                                             Mass                                                              .sup.1 H NMR                                                                              Spectrum                                 Ex.  Ra.         Form    (ppm)       (m/e M.sup.+)                            ______________________________________                                        34   4Cl--Ph     oil     7.2-7.7 (9H,m)                                                                            400,402                                                           5.70 (1H,s) (3:1)                                    35   4F-Ph       oil     6.95-7.65 (9H,m)                                                                          384                                                               5.70 (1H,s)                                          36   2Cl--Ph     oil     7.8-8.0 (1H,m)                                                                            400,402                                                           7.25-7.6 (8H,m)                                                                           (3:1)                                                             6.17 (1H,s)                                          37   3Cl--Ph     oil     7.0-7.6 (9H,m)                                                                            400,402                                       (iii)               5.7 (1H,s)  (3:1)                                    38   3Cl--Ph     oil     7.0-7.6 (9H,m)                                                                            400,402                                       (iv)                5.7 (1H,s)  (3:1)                                    39   3Cl--Ph     oil     7.0-7.6 (9H,m)                                                                            400-402                                       (v)                 5.7 (1H,s)  (3:1)                                    40   2Me--Ph     oil     7.7 (1H,dd; J10,3)                                                                        380                                                               7.0-7.5 (8H,m)                                                                5.85 (1H,s)                                                                   2.5 (3H,s)                                           41   4Me--Ph     solid   7.0-7.5 (9H,m)                                                                            380                                                       m.p.    5.65 (1H,s)                                                           93-95   2.35 (3H,s)                                                           °C.                                                   42   4NO.sub.2 --Ph                                                                            oil     8.25 (2H,d; J8)                                                                            429*                                                             7.7 (2H,d; J8)                                                                7.25 (5H,s)                                                                   5.75 (1H,s)                                          43   4MeO--Ph    oil     7.6-8.2 (1H,CO.sub.2 H)                                                                   396                                                               7.5 (2H,d; J8.5)                                                              7.35 (5H,s)                                                                   6.9 (2H,d; J8.5)                                                              5.6 (1H,s)                                                                    3.8 (3H,s)                                           44   3Br--Ph     oil     7.15-8.2 (10H,m;                                                                           462,464*                                                         aromatic + CO.sub.2 H)                                                                    (1:1)                                                             5.65 (1H,s)                                          45   1-naphth    oil     8.25 (1H,m) 416                                                               8.0-7.7 (3H,m)                                                                7.2-7.7 (9H,m;                                                                aromatic + CO.sub.2 H)                               46   2-naphth    solid   7.0-8.0 (13H,m;                                                                           416                                                       m.p.    aromatic + CO.sub.2 H)                                                118-    5.85 (1H,s)                                                           119° C.                                               47   3Me--Ph     oil     7.1-7.5 (10H,m;                                                                           380                                                               aromatic + CO.sub.2 H)                                                        5.85 (1H,s)                                          48   3,4Cl.sub.2 --Ph                                                                          oil     7.1-8.5 (9H,m;                                                                            452,454                                                           aromatic + CO.sub.2 H)                                                                     456*                                                             5.65 (1H,s)                                          49   4CF.sub.3 --Ph                                                                            oil     7.75 (4H,s) 434                                                               7.3 (5H,s)                                                                    5.8 (1H,s)                                           50   3CF.sub.3 --Ph                                                                            oil     7.0-8.8 (10H,m;                                                                            452*                                                             aromatic + CO.sub.2 H)                                                                    ,                                                                 5.75 (1H,s)                                          51   3MeO--Ph    oil     9.0-10.0 (1H;                                                                             396                                                               br CO.sub.2 H)                                                                7.05-7.5 (8H,m)                                                               6.85 (1H dd; J8,2)                                                            5.7 (1H,s)                                                                    3.8 (3H,s)                                           52   2F--Ph      oil     8.0-9.4 (1H,                                                                               402*                                                             br CO.sub.2 H)                                                                7.75 (1H,m)                                                                   6.95-7.5 (8H,m)                                                               6.05 (1H,s)                                          53   2MeO--Ph    oil     7.8 (1H,dd; J8,2)                                                                         396                                                               7.2-7.5 (6H,m)                                                                7.05 (1H,dt;                                                                  J 1.5,8)                                                                      6.9 (1H,dd;                                                                   J 1.5,8)                                                                      6.07 (1H,s)                                                                   3.85 (3H,s)                                          54   4Br--Ph     oil     7.5 (4H,m)   462,464*                                                         7.2 (5H,m)                                                                    5.7 (1H,s)                                           55   4CN--Ph     oil     8.0-9.2 (1H;                                                                               409*                                                             br CO.sub.2 H)                                                                7.7 (4H,m)                                                                    7.3 (5H,m)                                                                    5.75 (1H,s)                                          56   3F--Ph      oil     8.0-9.0 (1H,                                                                              384                                                               br CO.sub.2 H)                                                                6.8-7.4 (9H,m)                                                                5.7 (1H,s)                                           57   2CF.sub.3 --Ph                                                                            oil     7.3-8.7 (1H;                                                                               452*                                                             br CO.sub. 2 H)                                                               8.1 (1H; d,J8)                                                                7.2-7.8 (8H,m)                                                                6.05 (1H,s)                                          58   4MeS--Ph    oil     8.3-9.2 (1H,                                                                              412                                                               br CO.sub.2 H)                                                                7.5 (d, J8)                                                                   7.35 (s) -9H                                                                  7.25 (d,J8)                                                                   5.7 (1H,s)                                                                    2.5 (3H,s)                                           59   3HO--Ph     oil     6.65-7.5 (9H,m)                                                                           382                                                               6.0-6.65 (2H,br s)                                   60   4AcNH--Ph   solid   8.9 (1H,br NH)                                                                             441*                                                     m.p.    7.4-7.7 (4H,m)                                                        157-    7.1-7.4 (5H,m)                                                        159° C.                                                                        5.65 (1H,s)                                                                   2.1 (3H,s)                                           61   F.sub.5 --Ph                                                                              oil     10.2-10.6 (1H,                                                                            456                                                               br CO.sub.2 H)                                                                7.1-7.6 (5H,m)                                                                6.1 (1H,s)                                           62   3,4-OCH.sub.2 O--                                                                         oil     7.2-7.4 (5H,m)                                                                            410                                           Ph                  7.1 (1H,br s)                                                                 7.05 (1H,dd; J8,2)                                                            6.8 (1H,dd;J8,2)                                                              5.95 (2H,s)                                                                   5.65 (1H,s)                                          63   2,4-Me.sub.2 Ph                                                                           oil     7.55 (1H,d,J8)                                                                            394                                                               7.2-7.4 (5H,m)                                                                7.05 (1H,dd,J8,2)                                                             7.0 (1H,br s)                                                                 5.8 (1H,s)                                                                    2.4 (3H,s)                                                                    2.3 (3H,s)                                           64   3,4-(CH.sub.2 --                                                                          oil     7.1-7.6 (8H,m)                                                                            408                                           OCH.sub.2)--Ph      5.75 (1H,s)                                                                   5.2 (4H,s)                                           ______________________________________                                         Notes:                                                                        (i) NMR: all proton NMR were determined in CDCl.sub.3 at 90 MHz except Ex     60 which was determined in d.sub.6acetone; signals are given in the Table     for ring B protons and the fragment Ra.CH, but the spectra additionally       contain signals at 1.4 -2.8 (9H,m), 4.1-4.3 (2H,m) and 5.1-5.5 (3H,m)ppm;     coupling constants (J) are given in Hz;                                       (ii) MS: all mass spectra contained additional characteristic signals         corresponding to m/e = M--Ra.CHO; those marked with an asterisk (*) were      determined by chemical ionisation using ammonia and corresponding to m/e      M + NH.sub.4  rather than m/e = M; relative strengths of isotopic values      are given in parentheses;                                                     (iii) racemic (±) form;                                                    (iv) dextrorotatory (+) enantiomer; [α].sub.D.sup.20 = +88°      (-c. 2.05, MeOH);                                                             (v) laevorotatory (-) enantiomer; [α].sub.D.sup.20 = -92°        (-c. 1.52, MeOH;                                                         

The aldehyde starting material for Example 64 was obtained as follows:

To a solution of 1,3-dihydro(5-benzo[c]furyl)methanol (1.265 g.) in drymethylene chloride (10 ml.) was added pyridinium dichromate (3.23 g.) inone portion. The dark mixture was stirred for 90 minutes and dilutedwith ether (100 ml.). The suspension obtained was separated byfiltration through diatomaceous earth. The residue was washed with ether(50 ml.) and the combined filtrate and washings evaporated. The residualoil was purified by flash column chromatography, eluting with 40% v/vethyl acetate/hexane to give 1,3-dihydro(5-benzo[c]furyl)carboxaldehydeas a semi-solid mass (0.66 g.); NMR: 9.95 (1H,s); 7.7-7.8 (2H,m); 7.3(1H d,J-8H) and 5.1 (4H,s) ppm.

EXAMPLES 65-69

Using a similar procedure to that described for Example 33 but startingfrom the appropriate aldehydes of formula Ra.CHO, the following acids offormula Ib were obtained in yields of 30-80%:

(EXAMPLE 65)

Ra=isopropyl, Rb=H, benzene ring B is unsubstituted; as an oil; NMR:10.0 (1H, br s), 7.1-7.5 (5H,m), 5.0-5.6 (2H,m), 4.9 (1H,d,J=1 Hz), 4.5(1H,d,J=3 Hz), 3.8-4.2 (2H,m), 1.3-2.7 (10H,m) and 1.05 (6H,d,J=8 Hz)ppm; m/e: 331 (M⁺ +H); using isobutyraldehyde in place of benzaldehydeat room temperature for 3 days;

(EXAMPLE 66)

Ra=pentyl, Rb=H, benzene ring B is unsubstituted; as an oil; NMR:7.2-7.4 (5H,m), 5.2-5.5 (2H,m), 4.9 (1H,d,J=2 Hz), 4.7 (1H,t,J=3 Hz),3.7-4.2 (2H,m) and 0.7-2.6 (20H,m) ppm; m/e: 359 (M⁺ +H); using hexanalin place of benzaldehyde;

(EXAMPLE 67)

Ra=Octyl, Rb=H, benzene ring B is unsubstituted; as an oil; NMR: 7.1-7.4(5H,m), 5.1-5.5 (2H,m), 4.9 (1H,d, J=1 Hz), 4.75 (1H,t, J=3 Hz), 3.7-4.2(2H,m), 1.05-2.6 (23H,m) and 0.85 (3H,br t) ppm; m/e: 403 (M⁺ +H);starting from 1-nonanal in place of benzaldehyde;

(EXAMPLE 68)

Ra=2-chlorophenyl, Rb=H, benzene ring B is 2-fluorophenyl; as an oil;NMR: 1.4-2.8 (9H,m), 4.1-4.3 (2H,m), 5.1-5.5 (3H,m), 6.05 (1H,s), 7.22(7H,m) and 7.82 (1H,m) ppm; starting from 2-chlorobenzaldehyde and5(Z)-7-[2,2-dimethyl-4-(2-fluorophenyl)-1,3-dioxan-cis-5-yl]heptenoicacid;

(EXAMPLE 69)

Ra=2-methylphenyl, Rb=H, benzene ring B is 2-methoxyphenyl; as an oil;NMR: 1.4-2.8 (9H,m), 2.44 (3H,s), 3.85 (3H,s), 4.0-4.3 (2H,m), 5.1-5.5(3H,m), 5.87 (1H,s) and 7.28 (8H,m) ppm; starting from2-methylbenzaldehyde and5(Z)-7-[2,2-dimethyl-4-(2-methoxyphenyl)-1,3-dioxan-cis-5-yl]heptenoicacid.

EXAMPLE 70

Using a similar method to that described in Example 4, there wasobtained5(Z)-7-[2,2-diethyl-4-(2-fluorophenyl)-1,3-dioxan-cis-5-yl]heptenoicacid NMR: 0.7-1.2 (6H,m), 1.3-2.6 (13H,m), 3.7-4.3 (2H,m), 5.1-5.5(3H,m), 7.11 (3H,m) and 7.52 (1H,m) ppm; as an oil in 54% yield startingfrom [2,2-diethyl-4-(2-fluorophenyl)-1,3-dioxan-cis-5-yl]acetaldehyde,itself obtained in 64% yield as an oil with IR absorption at 1720 cm⁻¹by oxidation of(4,5-cis)-5-allyl-2,2-diethyl-4-(2-fluorophenyl)-1,3-dioxane. The lattercompound showed significant NMR aromatic proton signals at 7.15 (3H,m)and 7.58 (1H,m) ppm and was obtained in 23% yield fromerythro-2-allyl-1-(2-fluorophenyl)-1,3-propanediol using an analogousprocedure to that described for the corresponding starting material inExample 4, but starting from (4,5-cis)-5-allyl-2,2-diethyl-4-(2-fluorophenyl)-1,3-dioxane.

EXAMPLE 71

In a similar manner to example 1, but starting from[2,2-bis(trifluoromethyl)-4-phenyl-1,3-dioxan-cis-5-yl]acetaldehyde,there was obtained5(Z)-7-[2,2-bis(trifluoromethyl)-4-phenyl-1,3-dioxan-cis-5-yl]heptenoicacid as a colourless oil in 65% yield; NMR: 1.3-2.6 (9H,m), 4.0-4.5(2H,m), 4.9-5.6 (3H,m) and 7.1-7.5 (5H,m) ppm; m/e: 426 (M⁺).

The starting material was obtained as follows:

(a) A solution of p-toluenesulphonyl chloride (15.8 g.) in methylenechloride (50 ml.) was added over an hour to a stirred solution of crudeerythro-2-allyl-1-phenyl-1,3-propanediol (15.4 g.) in methylenechloride. (150 ml.) containing triethylamine (12.0 ml.) and kept at 4°C. The mixture was stirred a further 1 hour at 4° C. and then for 64hours at room temperature before being diluted with ether (500 ml.). Thesubsequent mixture was washed successively with water (100 ml.) 5% w/vsodium hydrogen carbonate solution (100 ml.), water (2×100 ml.) andsaturated brine solution (100 ml.), then dried (MgSO₄) and concentratedto give an oil which on column chromatography, eluting with 10% v/vethyl acetate/hexane, gave 3-(erythro-2-allyl-1-phenyl-1,3-propanediol)p-toluenesulphonate ester (X), as a colourless oil in 69% yield; NMR:1.8-2.3 (4H,m), 2.4 (3H,s), 3.7-4.2 (2H,m), 4.7-5.0 (3H,m), 5.35-5.8(1H,m), 7.2-7.4 (7H,m) and 7.75 (2H, d,J=8 Hz) ppm.

(b) A solution of the ester (X) (3.46 g.) in dry ether (10 ml.)containing anhydrous p-toluenesulphonic acid (5 mg.) was added over 10minutes to a stirred solution of hexafluoroacetone (prepared from 3.0ml. of the sesquihydrate) at -70° C. The mixture was stirred for 21/2hours at -70° C. and then allowed to warm to room temperature withstirring for 16 hours. The solvent was evaporated and the residual oildissolved in anhydrous ether (50 ml.) and sodium hydride (0.36 g.) wasadded in portions. The stirred mixture was heated under reflux for 1hour, cooled, and treated with ethanol (2 ml.) and ether (50 ml.). Thismixture was washed with water (4×15 ml.), dried (MgSO₄) and evaporated.The residual oil gave, on column chromatography eluting with 1.5% v/vethyl acetate/hexane,(4,5-cis)-5-allyl-2,2-bis(trifluoromethyl)-4-phenyl-1,3-dioxane (Y) as acrystalline solid (61%); m.p. 34°-35° C. NMR: 1.6-2.5 (3H, m), 4.1-4.5(2H,m), 4.8-5.7 (4H,m) and 7.1-7.4 (5H,m) ppm; m/e: 340 (M⁺).

(c) Ozone was passed through a solution of the dioxane (Y) (1.70 g.) inethyl acetate (100 ml.) at -78° C. until a permanent blue colourdeveloped. The solution was then flushed with argon until colourless. Asolution of triphenylphosphine (1.97 g.) in ethyl acetate (20 ml.) wasthen added and the mixture was stirred for 1 hour at -78° C. and thenovernight at 4° C. This mixture was evaporated and the residue waspurified by column chromatography, eluting with 15% v/v ethylacetate/hex ane to give[2,2-bis(trifluoromethyl)-4-phenyl-1,3-dioxan-cis-5-yl]acetaldehyde as acrystalline solid, m.p. 52.5°-53.5° C. in 93% yield; NMR: 2.15-3.1(3H,m), 4.0-4.7 (2H,m), 5.55 (1H, br s), 7.15-7.55 (5H,m) and 9.55(1H,s) ppm; m/e: 342 (M⁺).

EXAMPLES 72-73

In a similar manner to that described in Example 71, there wereprepared:

5(Z)-7-([2,4,5-cis]-2-trifluoromethyl-4-phenyl-1,3-dioxane-5-yl)heptenoicacid (Example 72) as a crystalline solid, m.p. 87.5°-8.5° C., in 76%yield; NMR: 1.2-2.7 (9H,m), 3.8-4.3 (2H,m), 4.95-5.6 (4H,m), 7.1-7.4(5H,m) and 9.25 (1H br s) ppm; m/e: 357 (M⁺ -H); and

5(Z)-7-([2,4-trans,4,5-cis]-2-trifluoromethyl-4-phenyl-1,3-dioxane-5-yl)heptenoicacid (Example 73) as a crystalline solid, m.p. 62°-64° C., in 96% yield;NMR: 1.5-2.6 (9H,m), 3.85-4.5 (2H,m), 5.05-5.6 (4H,m), 7.1-7.5 (5H,m)and 9.85 (1H,br s) ppm; m/e: 358 (M⁺). The following intermediates wereobtained:

(i) [2,4,5-cis]-2-trifluoromethyl-4-phenyl-1,3-dioxan-5-yl)acetaldehydeas an oil in 96% yield; NMR: 2.15-3.2 (3H,m), 4.0-4.2 (2H,m), 5.0-5.2(2H,m),7.15-7.5 (5H,m) and 9.6 (1H,s) ppm; m/e: 274 (M⁺); and

(ii)([2,4-trans,4,5-cis]-2-trifluoromethyl-4-phenyl-1,3-dioxan-5-yl)acetaldehydeas a crystalline solid, m.p. 62°-63° C., in 92% yield; NMR: 2.2-3.05(3H,m), 3.8-4.65 (2H,m), 5.1-5.55 (2H,m), 7.15-7.5 (5H,m) and 9.6 (1H,s)ppm.

These aldehydes were obtained by oxidation of the corresponding5-allyl-1,3-dioxanes as described for example 71. These dioxanes wereobtained together by substituting trifluoroacetaldehyde forhexafluoroacetone in procedure (b) of Example 71, followed bychromatographic separation on silica using 2% v/v ethyl acetate/hexaneas eluant, resulting in the isolation of:

(iii) [2,4,5-cis]-5-allyl-2-trifluoromethyl-4-phenyl-1,3-dioxane in 49%yield as a crystalline solid, m.p. 60°-61° C.; NMR: 1.6-1.95 (2H,m),2.1-2.6 (1H,m), 3.9-4.4 (2H,m), 4.8-5.15 (4H,m), 5.3-5.8 (1H,m) and7.2-7.4 (5H,m) ppm; m/e: 272 (M⁺); and

(iv) [2,4-trans,4,5-cis]-5-allyl-2-trifluoromethyl-4-phenyl-1,3-dioxanein 15% yield as a crystalline solid m.p. 78°-79° C.; NMR: 1.65-2.45(3H,m), 3.9-4.5 (2H,m), 4.8-5.8 (5H,m) and 7.25-7.45 (5H,m) ppm; m/e 272(M⁺).

EXAMPLE 74

To a solution of methyl5(Z)-7-([2,4,5-cis]-2-chloromethyl-4-phenyl-1,3-dioxan-5-yl)heptenoate(300 mg.) in methanol (10 ml.) was added aqueous potassium hydroxide(2M,2.6 ml.). The mixture was stirred for 41/2 hours and diluted withwater (50 ml.), then extracted with ether (2×20 ml.) and the extractsdiscarded. The aqueous layer was acidified to pH 5 (2M hydrochloricacid) and extracted with ether (3×20 ml.). The extracts were dried(MgSO₄) and evaporated to give an oil which on column chromatography,eluting with 85:12:2 (by volume) toluene/ethyl acetate/acetic acid gave5(Z)-7-([2,4,5-cis]-2-chloromethyl-4-phenyl-1,3-dioxan-5-yl)heptenoicacid in 92% yield as a crystalline solid; m.p. 58°-61° C.; NMR: 1.4-2.7(9H,m), 3.65 (2H,d, J=4 Hz), 3.85-4.3 (2H,m), 4.85-5.55 (4H,m), 7.2-7.4( 5H,m) and 8.4 (1H,br s) ppm.

EXAMPLE 75

A solution containing methyl5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoate (584 mg.),p-toluenesulphonic acid (10 mg.) and 2-chloro-1,1-dimethoxyethane (2ml.) was heated at 100° C. for 18 hours. The cooled reaction mixture wasdiluted with ether (80 ml.) and successively washed with 5% w/w sodiumhydrogen carbonate solution (2×10 ml.), water (3×10 ml.) and saturatedsodium chloride solution (1×10 ml.), then dried (MgSO₄) and evaporatedto give an oil, which on column chromatography, using 2% v/v ethylacetate/toluene as eluant, gave methyl5(Z)-7-(2,4,5-cis]-2-chloromethyl-4-phenyl-1,3-dioxan-5-yl)heptenoate asa colourless oil in 52% yield; NMR: 1.4-2.65 (9H,m), 3.6-3.8 (5H,m),3.8-4.25 (2H,m), 4.85-5.55 (4H,m) and 7.2-7.45 (5H,m) ppm; m/e: 351 (M⁺-H).

The starting material was obtained as follows:

An ethereal solution of diazomethane was added to a solution of5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid (3.99 g.)in dry ether (50 ml.) at 4° C., until a yellow colour persisted in themixture. A few drops of acetic acid were then added until effervescencehad ceased. The mixture was evaporated to give an oil which on columnchromatography using 70:30:2 (by volume) toluene/ethyl acetate/aceticacid as eluant, gave methyl5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoate as a colourlessoil in 81% yield; NMR: 1.4-2.4 (9H,m) 2.6-3.1 (2H,br s), 3.55-3.8(5H,m), 4.9-5.55 (3H,m) and 7.15-7.45 (5H,m) ppm.

EXAMPLES 76-79

Using a similar procedure to that described in Example 74, the followingcompounds were obtained by hydrolysis of the corresponding methylesters:

(EXAMPLE 76)

5(Z)-7-([2,4,5-cis]-2-cloroethyl-4-phenyl-1,3-dioxan-5-yl)heptenoic acidas a crystalline solid, m.p. 54°-54.5° C. in 92% yield; NMR: 1.4-2.6(11H,m), 3.75 (2H,t,J=7 Hz), 3.8-4.2 (2H,m), 4.9-5.55 (4H,m), 7.2-7.4(5H,m) and 9.8 (1H,br s) ppm;

(EXAMPLE 77)

5(Z)-7-(4'-phenyl-[4-methylcyclohexanespiro-2'-1,3-dioxan]-cis-5'-yl)heptenoicacid (isomer A*) as a colourless oil in 81% yield; NMR: 0.7-2.9 (21H,m),3.6-4.2 (2H,m), 4.9-5.6 (3H,m) and 7.1-7.5 (5H,m) ppm; m/e : 372 (M⁺);and

(EXAMPLE 78)

5(Z)-7-(4'-phenyl-[4-methylcyclohexanespiro-2'-1,3-dioxan]-cis-5'-yl)heptenoicacid (isomer B*) as a colourless oil in 53% yield; NMR: 0.7-2.9 (21H,m),3.6-4.4 (2H,m), 5.0-5.5 (3H,m) and 7.1-7.5 (5H,m) ppm; m/e: 372 (M⁺); [*Isomers A and B were obtained, respectively, by hydrolysis of the lesspolar and more polar isomers of methyl5(Z)-7-(4'-phenyl-[4-methylcyclohexanespiro-2'-1,3-dioxan]-cis-5'-yl)heptenoate,as seen on TLC analysis in 10% v/v ethyl acetate/hexane.]

(EXAMPLE 79)

5(Z)-7-([2,4,5-cis]-2-vinyl-4-phenyl-1,3-dioxan-5-yl)heptenoic acid as asolid, m.p. 40°-43° C., in 80% yield; NMR: 1.4-2.7 (9H,m), 3.8-4.3(2H,m), 5.05 (1H,d,J=3 Hz), 5.1-5.55 (4H,m), 5.6-5.7 (1H,m), 5.8-6.3(1H,m), 7.2-7.4 (5H,m) and 7.7 (1H,br s) ppm; m/e: 316 (M⁺).

EXAMPLES 80-82

Using a similar procedure to that described in Example 75, the followingesters were obtained from methyl5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoate:

(EXAMPLE 80)

methyl5(Z)-7-([2,4,5-cis]-2-chloroethyl-4-phenyl-1,3-dioxan-5-yl)heptenoate asa colourless oil in 63% yield; NMR: 1.4-2.6 (11H,m), 3.55-4.3 (7H,m),4.85-5.5 (4H,m) and 7.15-7.45 (5H,m) ppm; by replacing2-chloro-1,1-dimethoxyethane with 3-chloro-1,1-dimethoxypropane,carrying out the reaction at room temperature for 16 hours, andpurification by column chromatography on silica using 10% v/v ethylacetate/hexane as eluant;

(EXAMPLE 81)

methyl5(Z)-7-(4'-phenyl-[4-methylcyclohexanespiro-2'-1,3-dioxan]-cis-5'-yl)heptenoate(less polar isomer on TLC: SiO₂, 10% v/v ethyl acetate/hexane), as acolourless oil in 38% yield; NMR: 0.9 (3H,d), 1.0-2.7 (18H, m), 3.6(3H,s), 3.8 (1H,m), 4.05 (1H,m), 5.1-5.4 (3H,m) and 7.1-7.4 (5H,m) ppm;

(EXAMPLE 82)

methyl5(Z)-7-(4'-phenyl-[4methylcyclohexanespiro-2'-1,3-dioxan]-cis-5'-yl)heptenoate(more polar isomer on TLC: SiO₂, 10% v/v ethyl acetate/hexane) as acolourless oil in 28% yield; NMR: 0.9 (3H,d), 1.0-2.7 (18H,m), 3.6(3H,s), 3.7 (1H,d), 4.2 (1H,d), 5.15 (1H,d), 5.2 (1H,m), 5.3 (1H,m) and7.2-7.4 (5H,m) ppm; [Both Example 81 and 82 were obtained in the samereaction by replacing 2-chloro-1,1-dimethoxyethane with4-methylcyclohexanone (0.27 ml.) and trimethyl orthoformate (0.29 ml.),carrying out the reaction at room temperature for 2 hours, and purifyingthe crude product by column chromatography using 10% v/v ethylacetate/hexane as eluant.].

EXAMPLE 83

A solution containing5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoate (222 mg.),p-toluenesulphonic acid (5 mg.) and 3,3-dimethoxy-1-propene (0.2 ml.) intoluene (1 ml.) was stirred for 3 hours. Water (20 ml.) was added andthe mixture was extracted with ether (3×10 ml.). The combined organicextracts were washed successively with water (2×10 ml.) and saturatedbrine solution (1×50 ml.), dried (MgSO₄) and evaporated to give an oilwhich on column chromatography, using 20% v/v ethyl acetate/hexane aseluant, gave methyl 5(Z)-7-([2,4,5-cis]-2-vinylphenyl-1,3-dioxan-5-yl)heptenoate as a colourless oil in 48% yield,essentially pure by TLC analysis.

EXAMPLE 84

A solution containing5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-(2-methylphenyl)nonenoic acid(2.75 g.) and powdered potassium hydroxide (4.19 g.) in dimethylsulphoxide (23 ml.) was treated with dibromomethane (3.26 g.) withstirring under argon. Stirring was continued overnight. The mixture wasthen poured into ice-water (70 ml.), acidified to pH5 (2M hydrochloricacid), and extracted with ethyl acetate (3×50 ml.). The combinedextracts were washed with water and saturated brine, dried (MgSO₄) andevaporated to give an oil (2.8 g.) which was purified by columnchromatography using 80:20:2 by (volume) toluene/ethyl acetate/aceticacid to give 5(Z)-(4-[2-methylphenyl]-1,3-dioxan-cis5-yl)heptenoic acid(1.0 g.) as an oil which solidified on standing to give a crystallinesolid, m.p. 83°-86° C.; NMR: 7.1-7.5 (4H,m), 4.9-5.4 (5H,m), 3.8-4.1(2H,m), 1.5-2.65 (9H,m) and 2.25 (3H,s)ppm.

EXAMPLE 85

A solution containing sodium ethoxide (from sodium metal, 0.095 g.) inethanol (20 ml.) was treated with a solution of5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (0.12g.) in ethanol (20 ml.) and the mixture was stirred for 2 hours. Thesolvent was evaporated to leave a white powder which on crystallisationfrom dichloromethane/hexane gave sodium5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoate as whitecrystals, m.p. 160°-169° C. (decomposition),; microanalysis found:C,66.1; H,7.5%; Calculated (C₁₉ H₂₅ O₄ Na+1/4H₂ O):C,66.2; H,7.4%.

EXAMPLE 86-92

A solution containing5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (318mg.), 4-dimethylaminopyridine (122 mg.) and methanesulphonamide (95 mg.)in dry dichloromethane (20 ml.)was treated with a solution ofdicyclohexylcarbodiimide (206 mg.) in dichloromethane (2 ml.). Themixture was stirred Overnight, filtered, and the filtrate wasevaporated. The residual oil was partitioned between saturated aqueoussodium carbonate solution (50 ml.) and ether (50 ml.), and the aqueousphase was washed with more ether (2×25 ml.). The aqueous phase wasacidified with hydrochloric acid (2M) and extracted with ethyl acetate(3×25 ml.). The combined extracts were washed with saturated brine,dried (MgSO₄) and evaporated to give an oil which on columnchromatography, eluting with toluene/ethyl acetate/acetic acid (80:20:2v/v) gave N-methanesulphonyl-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenamide, as a colourless oil (100 mg.); NMR:1.2-2.5 (9H,m), 1.55 (6H,s), 3.25 (3H,s), 3.7-4.3 (2H,m), 5.1-5.5(3H,m), 7.1-7.4 (5H,br.s) and 8.4 (1H,br s)ppm.

Using a similar procedure the following N-alkanesulphonyl heptenamidesmay be obtained starting from the appropriate heptenoic acid of formulaIb:

(EXAMPLE 87)

N-methanesulphonyl-(5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenamide, asa solid, m.p. 85°14 87° C. in 71% yield; NMR: 1.2-2.5 (9H,m), 3.25(3H,s), 3.7-4.3 (2H,m), 4.8-5.5 (5H, m), 7.1-7.4 (5H,br s) and 8.4 (1H,br s)ppm; m/e: 368 (M⁺ +H);

(EXAMPLE 88)

N-methanesulphonyl-5(Z)-7-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenamide,as an oil in 70% yield; NMR: 0.7-1.3 (6H,m), 1.2-2.5 (13H,m), 3.25(3H,s), 3.7-4.3(2H,m), 5.1-5.5 (3H,m), 7.1-7.4 (5H,br s) and 8.5 (1H, brs )ppm; m/e 424 (M⁺ +H);

(EXAMPLE 89)

N-ethanesulphonyl-5(Z)-7-[4-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxan-cis-5-yl]heptenamide,as an oil in 77% yield: NMR: 1.35 (3H,t), 2.15 (15H,m), 3.45 (2H,q),4.03 (2H,m), 5.34 (3H,m), 7.12 (4H,m) and 7.50 (1H,m)ppm; m/e: 428 (M⁺+H);

(EXAMPLE 90)

N-ethanesulphonyl-5-(Z)-7-[4-(2-ethylphenyl)-2,2-dimethyl-1,3-dioxan-cis-5-yl]heptenamide,as an oil in 74% yield; NMR : 1.32 (6H,m), 1.64 (8H,m), 2.33 (9H,m),3.46 (2H,q), 4.07 (2H,m), 5.30 (3H,m), 7.23 (4H,m) and 7.50 (1H,m)ppm;:m/e 438 (M⁺ +H);

(EXAMPLE 91)

N-methanesulphonyl-5(Z)-7-[4-(2-ethylphenyl)-2,2-dimethyl-1,3-dioxan-cis-5-yl]heptenamide,as an oil in 81% yield; NMR: 1.13 (3H,t), 2.05 (17H,m), 3.16 (1H,s),3.83 (2H,m), 5.15 (3H,m), 7.1 (4H,m) and 7.37 (1H,m)ppm; m/e: 424 (M⁺+H);

(EXAMPLE 92

N-(1-methylethanesulphonyl)-5(Z)-[4-(2-ethylphenyl)-2,2-dimethyl-1,3-dioxan-cis-5-yl]heptenamide,as an oil in 73% yield; NMR: 1.4 (15H,m), 2.27 (11H,m), 3.83 (3H,m),5.18 (3H,m), 7.10(4H,m) and 7.46 (1H,m)ppm; m/e: 452 (M⁺ +H).

EXAMPLE 93

A solution containing erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonanoicacid (250 mg.), 2,2-dimethoxypropane (93 mg.) and p-toluenesulphonicacid (3 mg) in dry THF (10 ml.) was stirred for 30 minutes and thenallowed to stand overnight. Triethylamine (2 drops) was added and themixture was partitioned between ether (50 ml.) and water (50 ml.). Theorganic layer was washed with saturated brine (20 ml.), dried (MgSO₄)and evaporated to give an oil. Column chromatography, eluting with80:20:2 (by volume) toluene/ethyl acetate/acetic acid gave7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptanoic acid (180 mg.) asa colourless oil; NMR: 1.55 (6H,d), 0.9-2.4 (13H,m), 3.7-4.3 (2H,m),5.15 (1H,br s) and 7.3 (5H,br s )ppm.

The starting material was obtained as follows:

Hydrogenation of a solution of5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid (320 mg.)in ethyl acetate (20 ml.) using Adam's catalyst (30 mg.) for 2 hours atatmospheric pressure, followed by filtration and evaporation gaveerythro-9-hydroxy-8-hydroxymethyl-9-phenylnonanoic acid (317 mg.) as anoil, which was essentially pure by TLC analysis and was used withoutcharacterisation.

EXAMPLE 94

A portion (2.1 ml.) of a 0.5M solution of sodium thioethoxide inN,N-dimethylformamide was added under nitrogen to5(Z)-7-[2,2-dimethyl-4-(2-methoxyphenyl)-1,3-dioxan-cis-5-yl]heptenoicacid (104 mg.). The mixture was heated under reflux for 1.1 hours andthen diluted with ice-water to a total volume of 25 ml. The aqueousmixture was acidified to pH 4 with acetic acid and extracted with ethylacetate (2×15 ml.). The extracts were washed with saturated brine, dried(MgSO₄) and evaporated. The oil obtained was purified by columnchromatography on silica (12 g.) eluting with 80:20:2 (by volume)toluene/ethyl acetate/acetic acid to give5(Z)-7-[2,2-dimethyl-4-(2-hydroxyphenyl)-1,3-dioxan-cis-5-yl]heptenoicacid as an oil (25 mg.); NMR: 1.50 (6H,s), 2.22 (9H,m), 3.97 (2H,m),5.31 (3H,m), 6.98 (4H,m) and 8.38 (2H,s)ppm.

EXAMPLE 95

Potassium t-butoxide (7.4 g.) was added to a stirred mixture of(4-carboxybutyl)triphenyl phosphonium bromide (14.7 g.) and THF (170ml.) at 0°-5° C. under nitrogen. This mixture was added dropwise during10 minutes to a stirred solution of(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde (3.1 g.) in THF(50 ml.) at 0°-5° C. The mixture was stirred for 18 hours, poured ontoice (400 g.) and the solvent evaporated. The aqueous residue was washedwith ethyl acetate and insoluble material removed by filtration throughdiatomaceous earth. The filtrate was cooled to 0° C. and acidified to pH4 by addition of a saturated solution of sodium hydrogen tartrate (160ml.). The resultant emulsion was extracted with a 1:1 v/v mixture ofether and pentane.

The combined extracts were washed with saturated brine, dried (Na₂ SO₄)and evaporated to give an oil which was purified by chromatography usinga 3:1 v/v mixture of hexane and ether as eluant to give5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid as anoily solid (2.6 g.) m p. 79°-85° C. (2.6 g.), which was crystallisedfrom hexane (3 times) to give material of m.p. 86°-86.5° C.; ¹ H-NMR:1.55 (6H,s), 1.4-2.7 (9H,m), 3.80 (1H,dd), 4.15 (1H,br d), 5.0-5.5(3H,m), 7.30 (5H,s) and 11.0 (1H,br s )ppm; and ¹³ C-NMR (CDCl₃, 22.5Hz): 19.02 (axial CH₃), 21.67 (C7*,cis), 24.49 (C3*), 26.28 (C4*,cis),29.64 (equatorial CH₃), 33.37 (C2*), 39.66 (dioxan-C5), 62.52(dioxan-C6), 73.08 (dioxan-C4), 76.93 (CDCl₃), 98.98 (dioxan-C2), 125.31(phenyl-C2), 126.72 (phenyl-C4), 127.96 (phenyl-C3), 128.99 (C6*),130.18 (C5*), 140.80 (phenyl-C1) and 179.05 (C1*,CO₂ H)ppm (relative toTMS). [*refer to heptenoic acid carbon atoms]; i.e. essentially freefrom 5(E) isomer.

The starting aldehyde was obtained as follows:

A solution of osmium tetroxide (47 mg.) in water (6.0 ml.) was added toa stirred solution of (4,5-cis)-5-allyl-4-phenyl-1,3-dioxane (3.6 g.) inTHF (160 ml.). When the solution had become brown (5 minutes), it wastreated dropwise during 30 minutes with a solution of sodium periodate(13.7 g.) in water (90 ml.). The mixture was further stirred for 2 hoursand the solid removed by filtration. The filter cake was washed firstwith THF (15 ml.) and then with hexane (200 ml.). The aqueous phase ofthe filtrate was washed with hexane and the hexane washings combinedwith the organic phase of the filtrate. The solution obtained wasconcentrated in vacuo to low volume and the residual material dilutedwith further hexane. The solution obtained was washed with 10% w/vsodium sulphide solution, then with saturated brine and then dried (Na₂SO₄) and evaporated. The residual oil was purified by columnchromatography using 1:1 v/v hexane and ether as eluant. There was thusobtained (2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde as asolid, m.p. 69°-70° C. (after recrystallisation from hexane); NMR: 1.56(6H,s), 2.09-2.45 (2H,m), 2.87 (1H,m), 3.80 (1H,dd), 4.33 (1H,dt), 5.24(1H,d), 7.33 (5H,s) and 9.59 (1H,s)ppm.

EXAMPLE 96-97

Using a similar procedure to that described in Example 95, but startingfrom (+)-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde, therewas obtained(+)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(Example 96) as a syrup in 62% yield, [α]_(D) ²⁰ +99.5° (c,4.00, MeOH),having an identical NMR spectrum to that described for the racemic formin Example 95, and containing approximately 4% of the 5(E) isomer asjudged by ¹³ C-NMR spectroscopy.

Similarly,(-)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(Example 97) was obtained as a syrup in 65% yield, [α]_(D) ²⁰ -101° (c,4.24, MeOH), having an identical NMR spectrum to that described for theracemic form in Example 95, and containing about 5% of the 5(E) isomerby ¹³ C-NMR spectroscopy, starting from(-)-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde.

The starting enantiomeric aldehydes were obtained as follows:

(i) A solution of recrystallised(±)-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde (14.0 g.,m.p. 69°-70° C.) and (-)-ephedrine (9.9 g.) in benzene (200 ml.) washeated under reflux for 2.5 hours using a Dean and Stark apparatus forazeotropic removal of water. The solution was then evaporated and theresidual oil triturated with hexane to give solid which wasrecrystallised from hexane and petroleum ether (b.p. 30°-40° C.) to give(-)-[2,4,5-cis]-3,4-dimethyl-2-[(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)methyl]-5-phenyloxazolidine(A) as a crystalline solid (5.9 g.), m.p.104°-105° C., [α]_(D) ²⁰ -46°(c,4.23, acetone); microanalysis, found: C, 75.5; H,8.3; N,3.7%; C₂₄ H₃₁NO₃ requires : C, 75.5; H,8.2; N,3.7%; m/e: 382 (M⁺ +H).

(ii) A solution of anhydrous (+)-tartaric acid (2.98 g.) in acetone (299ml.) containing 1% v/v of water was added to a solution of the(-)-enantiomer (A, above) (7.6 g.) in acetone (50 ml.). The mixture wasstirred for 18 hours and the precipitate of ephedrine tartrate separatedby filtration. The residue was washed with acetone and the combinedwashings and filtrate were evaporated. This residue was partitionedbetween ether and water. The ethereal phase was dried (Na₂ SO₄) andevaporated. The resultant oil was purified by column chromatographyusing 3:1 v/v hexane and ether as eluant. There was thus obtained(-)-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde as a syrup(4.3 g.), [α]_(D) ²⁰ -58°(c, 4.20, MeOH), having an NMR spectrumidentical with that described for the racemic aldehyde in Example 95.

(iii) Using a similar procedure to (i) above but using (+)-ephedrine andstarting from 12.9 g. of the racemic aldehyde, there was obtained(+)-[2,4,5-cis]-3,4-dimethyl-2-[(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)methyl-5-phenyloxazolidine(B) as a crystalline solid (4.5 g.) m.p. 104°-105° C., [α]_(D) ²⁰ +46°(c,4.02, acetone); microanalysis, found: c 75.9; H,8.0; N,3.8%; C₂₄ H₃₁NO₃ requires: C, 75.5; H,8.2; N, 3.7%; m/e: 382 (M⁺ +H).

(iv) Using a similar procedure to (ii) above but using (+)-tartaric acidand the (+)-enantiomer (B, above) (7.9 g.), there was obtained(+)-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde as a syrup(4.4 g.), [α]_(D) ²⁰ +57° (c, 4.20, MeOH), having an NMR spectrumidentical with that described for the racemic aldehyde in Example 95.

EXAMPLES 98-99

A solution of(±)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(6.0 g., m.p. 84°-84.5° C.) and (-)-α-methylbenzylamine (1.14 g.) inether (100 ml.) was seeded with crystals of salt X (see below). Thecrystals which separated were collected by filtration and the motherliquor (A) retained.

The crystals, [α]_(D) ²¹ +45° C. (c,3.08 ,MeOH) were recrystallised bydissolution in the minimum volume of boiling methanol followed byaddition of ether (30 ml.)/g. of crystals). After fourrecrystallisations pure salt X was obtained as needles (B) (1.6 g.) ofconstant specific rotation [α_(D) ²⁰ +68.8° (c,3.14,MeOH) and m.p.123°-128° C. The recrystallisation mother liquors gave further crops ofsalt X of varying purity [α]_(D) ²⁰ +44° to +68°) and mother liquors(C).

The combined mother liquors (A) and (C) were evaporated. The residue wasdissolved in the minimum volume of cold methanol. The solution obtainedwas diluted with ether, washed three times with McIlvaine buffer of pH4.0, five times with water, dried (Na₂ SO₄) and evaporated. The residualoily solid [4.0 g., [α]_(D) ²⁰ -29.9° (c,3.60, MeOH] was dissolved inether (100 ml.) containing (+)- -methylbenzylamine (1.0 g.). Thesolution was seeded with salt Y (see below). The crystals [3.2 g.,[α]_(D) ²¹ -55.3° (c, 3.05, MeOH], which separated were recrystallisedfour times as described for salt X above to give pure salt Y as needles(D) (1.72 g.) of constant specific rotation [α]_(D) ²⁰ -68.7° C. (c,3.10, MeOH) and m.p. 123°-128° C.

Needles D (1.7 g., salt Y) were dissolved in the minimum volume ofmethanol and the solution diluted with ether. The solution was thenwashed three times with McIlvaine buffer of pH 4.0, five times withwater, dried (Na₂ SO₄) and evaporated. A solution of the residue inpentane (15 ml.) was then percolated through silica (0.6 g.). Thefiltrate and washings were combined and evaporated to give(-)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(Example 98) as a syrup (1.02 g.), [α]_(D) ²⁰ -105° (c,3.99, MeOH),having an identical NMR spectrum with that of the racemic acid describedin Example 95.

Similar treatment of needles B (1.6 g., salt X) yielded(+)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(Example 99) as a syrup (0.95 g), [α]_(D) ²⁰ +106° (c, 4.1, MeOH),having an identical NMR spectrum to that of the racemic acid describedin Example 95.

The starting seed crystals were obtained as follows:

A solution the (+)-acid (Example 96) (163 mg.) and(-)-α-methylbenzylamine (62 mg.) in ether (2 ml.) deposited thecorresponding salt X as prisms (201 mg.), m.p. 123°-128° C.(indefinite), [α]_(D) ²⁰ +67.8° (c, 3.17, MeOH).

Similarly, a solution of the (-)-acid (Example 97) (187 mg.) and(+)-α-methylbenzylamine (71 mg.) in ether (2 ml.) deposited thecorresponding salt Y as prisms (221 mg.), m.p. 123°-128° C.(indefinite), [α]_(D) ²⁰ -67.9° (c, 2.78, MeOH).

EXAMPLES 100-101

A mixture of (-)-5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoicacid (1.2 g.), 3,3-diethoxypentane (5 ml.), and p-toluenesulphonic acidmonohydrate (one crystal) was stirred for 18 hours. The mixture wasdiluted with ether, treated with triethylamine (2 drops) and evaporatedin vacuo. An ethereal solution of the residue was washed three timeswith water, dried (Na₂ SO₄) and evaporated to give an oil (1.4 g.). Thiswas chromatographed on silica. Elution of the column with mixtures ofhexane and ether (10:1 to 3:1) yields(-)-5(Z)-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(Example 100) as an oil (0.68 g.), [α]_(D) ²⁰ 82.5° (c, 4.22, MeOH)(containing 2.8% of the corresponding 5(E)isomer by ¹³ C NMRspectroscopy); ¹ H-NMR:0.86 (3H,s), 1.08 (3H,s), 1.45-1.95 (10H,m), 2.23(2H,t), 2.45 (1H,m), 3.80 (1H,dd), 4.13 (1H,br d), 5.10 (1H,d),5.02-5.52 (2H,m), 7.32 (5H,s) and 10.05 (1H, br s )ppm.

Using a similar procedure starting from(+)-(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid (0.6 g.)there was obtained(+)-5(Z)-(2,2-diethyl-4-phenyl-1,3,-dioxan-cis-5-yl)heptenoic acid(Example 101) as an oil (0.4 g.), [α]_(D) ²⁰ +82.7 (c,4.26, MeOH)(containing less then 3% of the corresponding 5(E) isomer by ¹³ C-NMRspectroscopy) and having an essentially identical ¹ H-NMR spectrum tothat of Example 100 above.

The necessary starting materials were obtained as follows:

(i) A solution of(-)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(1.45 g.) in a mixture of THF (45 ml.) and 1M hydrochloric acid (1.1ml.) was left at ambient temperature for 18 hours and then evaporated.An ethereal solution of the residue was washed repeatedly with wateruntil no ionic chloride was present in the washings, dried (Na₂ SO₄) andevaporated to give(-)-5-(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid as asyrup (1.23 g.) [α]_(D) ²⁰ -32° (c, 2.14, methanol). ¹ H-NMR: 1.4-2.2(7H,m), 2.86 (2H,t, J-7 Hz), 3.68 (2H,d), 4.8 (3H, br), 4.99 (1H,d,J=3.6 Hz), 5.2-5.6 (2H,m) and 7.33 (5H,s)ppm.

(ii) In a similar manner but starting from(+)-5(Z)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid(1.26 g.), there was obtained(+)-5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid as asyrup (1.1 g.), [α]_(D) ²⁰ +32° (c, 2.16, MeOH), having an essentaillyidentical ¹ H-NMR spectrum to that of the (-) isomer in (i) above.

The above procedures were also used to obtain the racemic (+) form of5(Z)-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid having anidentical ¹ H-NMR spectrum to that of the (-)- or (+)- enantiomers(Examples 100,101), starting from racemic5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-phenylnonenoic acid.

EXAMPLE 102

A solution of 5(Z)-7-[2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (500mg.) in absolute ethanol (10 ml.) containing 5% w/w palladium oncharcoal catalyst (100 mg.) was stirred under an atmospheric pressure ofhydrogen for 3 hours. The catalyst was separated by filtration throughkieselguhr and the filtrate was evaporated to give 5(Z) 7-[2,4,5-cis]-2-methyl -4-phenyl-1,3-dioxan-cis-5yl)heptanoic acid as acolourless oil in 99% yield; NMR: 0.8-1.8 (14H,m), 2.2 (2H,t,J=8 Hz),3.8-4.25 (2H,m), 7.14-7.4 (5H,m) and 8.5-9.3 (1H,br)pm; m/e: 307 (M⁺+H).

EXAMPLE 103

Aqueous potassium hydroxide (34 ml. of 40% w/v solution) was added to astirred solution of5(E)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenonitrile (831mg.) in freshly distilled ethylene glycol (34 ml.) under an argonatmosphere and the mixture heated under reflux for 3.5 hours. The cooledmixture was diluted with water (100 ml.) and methylene chloride (100ml.), and then stirred and acidified to pH 5 (2M hydrochloric acid). Theorganic phase was separated, dried (MgSO₄) and evaporated. The residuewas purified by flash chromatography eluting with 1:99 v/v acetic acidand ethyl acetate to give5(E)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid as anoil (454 mg.): ¹ H-NMR: 8.7-9.6 (1H,br,CO₂ H)m 7.0-7.5 (5H,m), 4.85-5.5(3H,m), 4.0 (2H,q, J=12 Hz) and 1.35-2.55 (15H,m; including s at 1.52and 1.54)ppm; ¹³ C-NMR: (CDCL₃ ; MHz) 178.94 (C1*), 140.80 (Ph,C1),130.78 (C5*), 129.70 (C6*), 128.02 (C6*), 128.02 (Ph,C3), 126.77(Ph,C4), 125.42 (Ph,C2), 99.03 (dioxane, C2), 78.39+76.93+75.52 (CDCl₃),73.08 (dioxane, C4), 62.63 (dioxane, C6), 39.55 (dioxane, C5), 33.21(C2*), 31.70 (C4*), 29.58 (equatorial CH₃), 27.09 (C7*), 24.38 (C3* and19.13 (axial CH₃) ppm [Note: asterisk values refer to the heptenoic acidmoiety]; m/e: 318 (M⁺), 303 (M-CH₃) and 260 [M-(CH₃)₂ CO].

The starting material was obtained as follows:

A solution of 2-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)acetaldehyde(518 mg.) in dry THF (10 ml.) was added over 30 minutes to a stirredsolution of vinyl magnesium bromide (3,4 ml of 1,3M solution intetrahydrofuran) in tetrahydrofuran (5 ml.), at 0° C. under anatmosphere of Argon. After further stirring at 0° C. for 1 hr, saturatedammonium chloride solution was added to quench the reaction. The mixtureobtained was separated and the aqueous phase was extracted with ether.The combined organic phases were dried (MgSO₄) and evaported. Theresidue was purified by flash chromatography, eluting with 1:1 v/v ethylacetate/hexane to give an epimeric mixture of3-hydroxy-4-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)-but-1-ene (A),as an oil (564 mg.) NMR: 7.3 (5H,s); 5.35-5.9 (1H,m); 4.8-5.3 (3H,m);and 0.8-2.2 (10H,m), including 2 s at 1.55 m+OH)ppm.

Propionic acid (7.4 micromole) was added to a solution of (A; 433 mg.)in trietyl orthoacetate (2.2 ml.). The mixture was stirred at 140°-145°C. with removal of ethanol by distillation during 1 hour. The cooledreaction mixture was evaporated and the residue purified by flashchromatography, eluting with 15:85 v/v ethyl acetate/hexane to giveethyl 4(E)-6-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)hexenoate (B) asan oil (329 mg.); NMR: 7.3 (5H,s), 5.1-5.5 (3H,m), 3.75-4.2 (4H,m;including q at 4.1, J=7 Hz), 2.0-2.6 (6H,m), 1.4-1.8 (7H,m; including sat 1.55) and 1.25 (3H, t,J-7 Hz)ppm.

A solution of B (2.593 g.) in anhydrous ether (15 ml.) was addeddropwise to a stirred suspension of lithium aluminium hydride (297 mg.)in anhydrous ether (60 ml ) cooled to 5° C. The mixture was stirred at5° C. for a further 1 hour. Water (40 ml.) was then added cautiously.The mixture was separated and the aqueous phase was extracted with ether(4×60 ml.). The combined ethereal phases were dried (MgSO₄), andevaporated. The residue was purified by flash chromatography, elutingwith 3:2 v/v ethyl acetate/hexane to give4(E)-6-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)hexenol (C) as an oil(2.22 g.) NMR: 7.1-7.45 (5H,m), 5.0-5.6 (3H,m), 3.95 (2H,q, J=12 Hz),3.05 (2H,t,J=9 Hz), 1.8-2.6 (4H,m) and 1.4-1.8 (10H,m)ppm.

Methanesulphonyl chloride (0.57 ml.) was added dropwise to a stirredsolution of triethylamine (1.0 m,.) and C (2.083 g.) in methylenechloride (25 ml. freshly filtered through a short column of basicalumina) cooled to 5° C. The stirred mixture was then allowed to warm upto room temperature during 2 hours. Ether (100 ml.) was then added. Themixture was washed successively with water, and saturated brine, and wasthen dried (MgSO₄) and evaporated. The residue was purified by flashchromatography using 3:2 v/v ethyl acetate/hexane to give4(E)-6-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)hexenolO-methanesulphonate as an oil (D) (2.176 g.) NMR: 7.3 (5H,s), 5.0-5.55(3H,m), 4.15 (2H,t,J=6 Hz) 3.85 (2H,q, J=12 Hz), 2.95 (3H,s) and1,4-2.65 (13H,m; including 2 s at 1.55)ppm.

Potassium cyanide (405 mg.) was added in portions to a solution of D(1.115 g.) in anhydrous dimethyl sulphoxide (20 ml.) under argon. Themixture was stirred at 75° C. for 2 hours, then diluted with water (15ml.). The resultant mixture was extracted with ether . The extracts werewashed with saturated brine, dried (MgSO₄) and evaporated. The residuewas purified by flash chromatography using 3:7 v/v ethyl acetate/hexaneas eluant to give5(E)-7-(2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenonitrile as anoil (687 mg.); NMR : 7.3 (5H,s), 5.0-5.5 (3H,m), 4.0 (2H,q,J=11 Hz),1.9-2.5 (5H,m) and 1,3-1.9 (10H, m, including 2 s at 1.50 )ppm.

EXAMPLE 104

The preparation of an oral dosage form is illustrated by the followingtablet formulation:

5(Z)-7-(2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (300parts);

lactose (56 parts;

maize starch (30 parts)

polyvinylpyrrolidone (10 parts); and

magnesium stearate (4 parts) obtained using a standard wet granulationand compression procedure [all parts by weight]. The lactose may bereplaced by an alternative filler such as calcium phosphate, the maizestarch by an alternative disintegrant such as calciumcarboxymethylcellulose, and the polyvinylpyrrolidone by an alternativebinder such as gelatine, if desired.

Similarly the active ingredient may be replaced by another compound offormula I described herein. The tablets may be enteric coated byconventional means, for example to incorporate a coating of celluloseacetate phthalate. ##STR2##

What is claimed is:
 1. A 5-allyl-4-phenyl-1,3-dioxane derivative of theformula VII:wherein Ra and Rb are independently hydrogen, (2-6C)alkenyl,(1-8C) alkyl optionally bearing up to three halogeno substitutents,pentafluorophenyl, carbocyclic aryl or carbocyclic aryl(1-4C)alkyl, thelatter two of which may optionally bear up to three substituentsselected from halogeno, (1-6C)alkyl, (1-6C)alkoxy, (1-4C)alkylenedioxy,trifluoromethyl, cyano, nitro, hydroxy, (2-6C)alkanoyloxy, (1-6C)alkylthio, (1-6C)alkanesulphonyl, (1-6C)alkanoylamino, andoxapolymethylene of 2 to 4 carbon atoms, provided that when both Ra andRb are alkyl or alkenyl, the total number of carbon atoms in Ra and Rbtaken together is 8 or less; or Ra and Rb together form polymethylene of2 to 7 carbon atoms, optionally bearing one or two (1-4C)alkylsubstituents; benzene ring B optionally bears one or two substituentsselected from halogeno, (1-6C)alkyl, (1-6C)alkoxy, hydroxy,(1-6C)alkanoyloxy, (1-6C)alkanoylamino, trifluoromethyl and nitro; andthe substituents at positions 4 and 5 of the dioxane ring havecis-relative stereochemistry.
 2. A compound according to claim 1 whereinRa and Rb are:(i) independently hydrogen or (1-4C)alkyl, optionallybearing 1 to 3 halogeno substituents; (ii) one of the two is hydrogen or(1-4C)alkyl, and the other is phenyl, naphthyl or phenyl-(1-4C)alkyl,optionally bearing 1 or 2 substituents selected from halogeno,(1-4C)alkyl, (1-4C)alkoxy, (1-4C) alkylenedioxy, trifluoromethyl, cyano,nitro, hydroxy, (2-4C)alkanoyloxy, (1-4C)alkylthio,(1-4C)alkanesulphonyl, (1-4C)alkanylamino and oxapolymethylene of 2 to 4carbon atoms, or pentafluorophenyl; (iii) one of the two is hydrogen andthe other is (5-8C)alkyl or (2-6C)alkenyl; or (iv) both together formpolymethylene of 2 to 7 carbon atoms optionally bearing a (1-4C)alkylsubstituent; and benzene ring B optionally bears a single substituentlocated at the 2-position selected from halogeno, (1-4C)alkyl,(1-4C)alkoxy, hydroxy, (2-4C)alkanoyloxy, (1-4C)alkanoylamino andtrifluoromethyl, or bears a 3-halogeno substituent; and the substituentsat positions 4 and 5 of the dioxane ring have cis-relativestereochemistry.
 3. A compound according to claim 1 wherein:(i) Ra andRb are both hydrogen, methyl, ethyl, propyl, butyl or trifluoromethyl;(ii) one of Ra is hydrogen and the other is trifluoromethyl,chloromethyl, benzyl, isopropyl, hexyl, octyl, phenyl optionally bearing1 or 2 fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, hydroxy,cyano, methylthio or acetamido, phenyl bearing methylenedioxy ormethyleneoxymethylene, pentafluorophenyl, 1-naphthyl or 2-naphthyl; or(iii) Ra and Rb together form trimethylene, tetramethylene,pentamethylene, hexamethylene or a group of the formula:

    --CH.sub.2 CH.sub.2.CHCH.sub.3.CH.sub.2 CH.sub.2 --;

and benzene ring B is phenyl; 2-fluorophenyl, 2-chlorophenyl2-bromophenyl, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl,2-methoxyphenyl, 2-hydroxyphenyl, 3-fluorophenyl or 3-chlorophenyl.
 4. Acompound according to claim 2 wherein:(i) Ra and Rb are both hydrogen,methyl, ethyl, propyl, butyl, or trifluoromethyl; (ii) Ra and Rbtogether form trimethylene, tetramethylene, pentamethylene,hexamethylene or a group of the formula:

    --CH.sub.2 CH.sub.2.CHCH.sub.3.CH.sub.2 CH.sub.2 --; or

(iii) Ra is (3-8C)alkyl, trifluoromethyl, chloromethyl, 2-chloroethyl,pentafluorophenyl, or phenyl, benzyl or naphthyl, the last three ofwhich may optionally bear 1 or 2 halogeno, (1-4C)alkyl, (1-4C)alkoxy,trifluoromethyl, hydroxy, cyano, (1-4C)alkylthio or (1-4C)alkanoylaminosubstituents, or a methylenedioxy or methyleneoxymethylene substituent,and Rb is hydrogen; benzene ring B is unsubstituted or is 2-halogeno-,2-(1-4C)alkyl-, 2-(1-4C)alkoxy-, 2-hydroxy- or 3-halogeno-phenyl; Ra andthe substituents at the 4 and 5-positions of the dioxane ring havecis-relative stereochemistry; and the carbon atoms adjacent to thevinylene group have the indicated cis-relative stereochemistry.
 5. Acompound according to claim 3 wherein Ra and Rb have the meaningsdefined in (i) and (ii) of claim 3; or Ra is isopropyl, butyl, hexyl,octyl, trifluoromethyl, chloromethyl, 2-chloroethyl, pentafluorophenyl,benzyl, naphthyl or phenyl optionally bearing 1 or 2 fluoro, chloro,bromo, methyl, methoxy, trifluoromethyl, hydroxy, cyano, methylthio oracetamido substituents, or bearing a methylenedioxy ormethyleneoxymethylene substituent, and Rb is hydrogen; and benzene ringB is unsubstituted or bears a 2-fluoro, 2-chloro,2-bromo, 3-fluoro,3-chloro, 2-methyl, 2-ethyl, 2-isopropyl, 2-methoxy, or 2-hydroxysubstituent.
 6. A compound according to claim 4 wherein Ra, Rb andbenzene ring B are selected from the following combinations:

    ______________________________________                                        No.    Ra             Rb       Benzene Ring B                                 ______________________________________                                        1      methyl         methyl   3-fluorophenyl                                 2      methyl         methyl   3-chlorophenyl                                 3      methyl         methyl   2-methoxyphenyl                                4      methyl         methyl   2-methylphenyl                                 5      methyl         H        phenyl                                         6      trifluoromethyl                                                                              H        phenyl                                         7      isopropyl      H        phenyl                                         8      ethyl          ethyl    phenyl                                         9      ethyl          ethyl    2-fluorophenyl                                 10     2-chlorophenyl H        phenyl                                         11     2-methylphenyl H        phenyl                                         12     2-ethylphenyl  H        phenyl                                         13     3-fluorophenyl H        phenyl                                         14     3-chlorophenyl H        phenyl                                         15     3-methylthiophenyl                                                                           H        phenyl                                         16     4-fluorophenyl H        phenyl                                         17     4-chlorophenyl H        phenyl                                         18     4-methoxyphenyl                                                                              H        phenyl                                         19     3,4-methylene  H        phenyl                                                dioxyphenyl                                                            20     3,4-(methylene-                                                                              H        phenyl                                                oxymethylene)-                                                                phenyl                                                                 21     methyl         methyl   2 hydroxyphenyl                                ______________________________________                                    

and from the following combinations;

    ______________________________________                                        No      Ra + Rb          Benzene Ring B                                       ______________________________________                                        22      pentamethylene   phenyl                                               23      hexamethylene    phenyl                                               24      (3-methyl)pentamethylene                                                                       phenyl                                               ______________________________________                                    